Normal Disposition of Oxazepam in Acute Viral Hepatitis and Cirrhosis HARRISON J. SHULLr Jr., M.D.f GRANT R. WILKINSON, Ph.D., RAYMOND JOHNSON, and STEVEN SCHENKER, M.D., Nashville, Tennessee
Oxazepam (Serax®) is a tranquilizer-sedative of the benzodiazepine group that is predominantly metabolized to a pharmacologically inactive glucuronide and subsequently excreted by way of the kidneys. We administered this drug as a single oral dose to seven patients with acute viral hepatitis, to six with cirrhosis, and to age-matched control subjects. Elimination half-life (jy2) and the apparent oral plasma clearance for the drug in patients with hepatitis and cirrhosis were comparable to values obtained in age-matched controls (P > 0.05). In addition, the apparent volume of distribution of oxazepam, its plasma binding, blood/plasma ratio, and the rate of urinary excretion of oxazepam, predominantly as the glucuronide, were comparable (P > 0.05) in the two groups of patients with liver disease and their respective controls. Unlike many other sedatives, oxazepam is eliminated normally in patients with parenchymal liver disease and therefore, on pharmacokinetic grounds, seems to be an excellent sedative for use in such persons.
PATIENTS with acute and chronic parenchymal liver disease may have impaired elimination of various sedatives and analgesics (1). Moreover, sedatives have been implicated as common precipitants of coma in patients with hepatocellular disease (2). Curiously, little has been published about the disposition and elimination of the benzodiazepines in patients with liver disease, despite their extensive use and significant metabolism by the liver. Recently, it was shown that the clearance of diazepam (Valium®) is reduced by almost half in patients with viral hepatitis and cirrhosis, and this causes a twofold prolongation in the elimination half-life of the drug (3). A systematic evaluation of the other benzodiazepines in patients with liver disease is, however, lacking. The present study assesses the effect of acute and chronic hepatic parenchymal disease on the elimination of oxazepam (Serax®), a benzodiazepine closely related chemically and pharmacologically to diazepam. This drug was chosen for evaluation for several reasons. First, oxazepam is gaining increasing clinical acceptance both in Europe and the U.S. (4). Second, unlike diazepam, it • From the Departments of Medicine (Gastroenterology) and Pharmacology, Vanderbilt University School of Medicine and the Veterans Administration Hospital, Nashville, Tennessee.
420
has been reported to have a relatively short elimination half-life and is predominantly metabolized by conjugation (5, 6) to form a glucuronide that is pharmacologically inactive and is excreted by way of the kidney. The ability of the liver to metabolize various substances by synthesis of their glucuronides has not been well studied in patients with hepatic disease. The formation of bilirubin is impaired in congenital nonhemolytic jaundice ( 7 ) , but this does not seem to be the case in viral hepatitis and cirrhosis ( 8 ) . Furthermore, only 3 of 12 patients with alcoholic cirrhosis had any marked prolongation in the serum half-life of chloramphenicol, and, even in these cases, the urinary recoveries of unchanged and conjugated drug were not different from those obtained in control subjects ( 9 ) . Similarly, patients with cirrhosis challenged with a single dose of salicylamide had no major impairment in the total excretion of glucuronic acid derivatives (10). On the other hand, patients with chronic hepatitis and cirrhosis showed an increase in the urinary excretion of N-acetyl-p-aminophenol but a decreased excretion of its glucuronide after administration of acetanilide (11). Despite this conflict and the heterogeneity of glucuronyl transferase enzymes ( 1 2 ) , it was not unreasonable to postulate that the elimination of oxazepam might not be significantly altered in the presence of liver dysfunction associated with viral hepatitis and cirrhosis. Finally, not only would such a situation have significant clinical importance but it would also permit additional interpretation of the effect of such diseases on the elimination of diazepam, since oxazepam is the terminal and major urinary metabolite of this drug ( 1 3 ) . Experimental Procedure STUDY SUBJECTS
Two experimental groups were studied, consisting of patients with acute viral hepatitis and those with cirrhosis. The group with hepatitis comprised 6 men and 1 woman, 19 to 32 years of age (mean, 24.5 years) and 50 to 80 kg in weight (mean, 63.3 kg). The diagnosis of acute viral hepatitis was based on typical clinical findings and laboratory data. Five of seven patients had a positive blood test for hepatitis B surface antigen (HBsAg) by radioimmunoassay, serum glutamic oxalacetic transaminase (SGOT) level was greater than 600 KU/ ml in all, and bilirubin value was above 5.5 mg/dl in all, with a high of 19 mg/dl. Liver biopsy was thought to be unnecessary to confirm the diagnosis. The group with cirrhosis comprised 6 men, 37 to 57 years of age (mean, 46.5 years) and 55 to 80 kg in weight (mean, 69.5 kg). Cirrhosis was diagnosed Annals of Internal Medicine 84:420-425, 1976
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by typical clinical findings and liver function tests and was confirmed in four of six patients by percutaneous liver biopsy. In the other two patients, who were not biopsied, extensive ascites was present. The cirrhosis was presumed (by history, negative blood HBsAg test, or morphologic data) to be due to alcoholism in all six patients. Of the patients with cirrhosis, four had experienced hepatic encephalopathy previously, two had ascites, two had esophageal varices, one had a portacaval and one a splenorenal shunt, and one was in the early stage of hepatorenal syndrome. With the exception of the last patient, all others with liver dysfunction had normal serum creatinine and blood urea nitrogen levels. All patients with viral hepatitis and four of six with cirrhosis had received no drugs or alcohol for at least 3 weeks before the study. Two patients with cirrhosis were on a diuretic regimen. These and other clinical laboratory features for both experimental groups are shown in Table 1. Since it has been shown that the disposition and elimination of the related drug, diazepam, are age-dependent (3), two separate control groups, age-matched to the hepatitis and cirrhosis groups, respectively, were investigated. The normal controls for the hepatitis patients comprised 7 men and 1 woman, 14 to 30 years of age (mean, 25.0 years) and 56.8 to 90 kg in weight (mean, 74.2 kg). The equivalent controls for the group with cirrhosis comprised 7 men, 45 to 84 years of age (mean, 53.6 years) and 64.0 to 90.0 kg in weight (mean, 80.2 kg). Without the 84-year-old control patient, who was studied to determine the effect of such advanced age on oxazepam metabolism, the mean age is reduced to 49.2 years. Because this man's data agreed with those of the others, it is included in the total control group for the patients with
cirrhosis. All control subjects were free of hepatic and renal dysfunction by clinical and laboratory evaluation, and all had taken no drugs or alcohol for at least 3 weeks before the study. PROTOCOL
After informed consent, oxazepam, 45 mg, was given orally in tablet form (Lot No. 1731963, Wyeth Laboratories, Philadelphia, Pennsylvania) to all persons except the two youngest and the one oldest control subject, who received 15 mg. The purpose of the reduced dosage was to minimize sedation in the oldest control patient, age 84, and to compare oxazepam pharmacokinetics in one elderly and two young normal persons. Prior (14) and present studies have established that the 15 and 45 mg doses are handled comparably by normal persons; hence, the data after normalization were pooled for the two doses. All subjects had fasted overnight before the study, and this state was maintained for the next 5 hours.' Venous blood samples were obtained at 0, 30, 60, 90, and 120 minutes, then every hour for 3 hours, followed by samples every 2 hours for 10 more hours. The blood samples were collected in heparinized tubes, and the plasma was obtained by centrifugation and frozen at - 1 0 °C until analyzed. Urine was collected every 8 hours for 2 days and the samples frozen until analyzed. In two patients with normal liver function who had undergone cholecystectomy, 45 mg of oxazepam were administered orally, and bile was then collected by T tube every 8 hours for 48 hours. Oxazepam, 15 mg, was also administered orally three times a day to two control subjects and two stable subjects with cirrhosis for 2 weeks. Blood samples were collected at the above intervals
Table 1 . Clinical and Hepatic Function Characteristics* of Patients with Acute Viral Hepatitis and Cirrhosis
Patients Age Weight
Plasma Oxazepam TJ UnTotal f changed f
yr kg Acute viral hepatitis 20 67.5 11 2 32 80.5 25 60.0 22 63.0 4t 25 68.2 5t 6 19 54.0 29 50.0 7J§ Cirrhosis 57 55.0 HI
n
h
Total Bilirubin
Alkaline Phosphatase
mg/dl
IU/ml
Serum Plasma AlbuGlutamic min Oxalacetic Transaminase (SGOT) g/dl
Prothrombin Time
Other Drugs
Other Findings
Patient Control
]sec
KU/ml
6.17 5.60 4.29 5.22 5.62 4.03 6.27
5.18 6.27 4.98 8.79 5.30 5.48 6.40
12.0 7.6 5.7 19.0 10.5 5.5 18.5
227 162 200 290 153 190 140
4.4 4.6 4.3 4.0 4.3 4.8 4.5
1390 850 1250 2200 650 1025 1460
10.5 10.2 11.0 9.8 9.8 12.0 13.0
10.4 10.1 11.0 11.0 9.2 11.5 12.0
6.01
7.06
1.0
72
3.7
56
11.2
10.1
2
37
56.0
7.01
7.47
1.4
352
2.7
98
11.7
10.2
311
45
78.0
5.44
6.67
1.9
196
3.6
106
12.8
9.7
4||
49
78.6
6.35
9.17
1.0
90
4.2
20
10.2
10.9
5
48
80.0
6.38
11.01
6.6
347
2.0
165
13.4
10.3
6||
43
56.0
3.80
5.24
1.4
352
2.7
98
11.7
10.2
. .• ... . .. ... ... ... . .. Post portacaval shunt, prior encephalopathy Ascites, prior Lasix* encephalopathy Aldactone* Muscle wasiong, . .. varices, prior encephalopathy Varices, prior . .. encephalopathy Ascites, Aldactone hepatorenal syndrome Postdistal splenorenal shunt . . .
* Normal upper limits for these liver function tests are total bilirubin, 1.0 mg/dl; alkaline phosphatase, 85 IU/ml; SGOT, 40 KU/ml. Lower limit for albumin is 3.5 g/dl. t Unchanged refers to the pharmacologically active parent drug; total refers to the sum of the unchanged oxazepam and oxazepam glucuronide. % Patient's blood positive for hepatitis Bantigen (HBsAg); in the other two persons with viral hepatitis, the test was negative. § Only woman in patient group. || Cirrhosis proved by percutaneous liver biopsy. Shu// et a/. • Oxazepam in Hepatitis and Cirrhosis
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capture detector, was used. The column was Pyrex glass (Corning Glass, Corning, New York), 1 m X 2 mm X 6.4 mm packed with 1.5% OV-220 on Gas Chrom Q, 100/120 mesh (Applied Science Laboratory, Inc., State College, Pennsylvania). Operating conditions included an oven temperature of 215 °C; injector temperature, 255 °C; detector oven temperature, 250 °C; and nitrogen flow rate, 30 ml/min. The concentration of oxazepam was obtained by calculating the ratio of the peak height of the drug to that of the internal marker, and then relating this to previously constructed linear calibration curves over the concentration range of 10 to 200 ng/ml. The plasma elimination half-lives (TVi) for unchanged and total oxazepam were determined from the 6- to 24-hour data by linear regression of the logarithm of the plasma concentration and time. The total area under each curve was estimated by the trapezoidal rule, and this permitted calculation of the apparent oral plasma clearance (AUCo) of oxazepam from the ratio of the administered dose to the area under the plasma level/time curve (17). Although the drug was administered orally, two estimates were obtained of oxazepam's apparent volume of distribution (Vd) with the realization that these calculations would be biased by the absorption process. The equations used for this purpose were the following: ... Vd(
Figure 1. Plasma concentration/time profile for unchanged and total oxazepam in the younger normal control group. The data are given as the mean ± SD of eight control subjects, whose mean age is 25 years. The lines were drawn by best visual fit.
after the first dose of Days 1, 7, and 14. The blood/plasma concentration ratio of oxazepam was determined on all of the zero time samples after the addition of drug to give a blood concentration of 40 ng/ml. The plasma binding of oxazepam was estimated by overnight equilibrium dialysis according to the method described by Evans, Nies, and Shand (15) and by using an external buffer concentration of 100 ng/ml. Analysis and Pharmacokinetic Measurements
Unchanged oxazepam in plasma, urine, and bile was determined by gas chromatography of its thermal degradation product (16) and by using electron capture detection. The biological sample (0.5 to 2.0 ml) was added to 2 ml of 1M phosphate buffer (pH 7.0) and 0.1 ml aqueous internal marker solution (Lorazepam®, 0.75 pg/ml). After adjusting the total volume to 8.1 ml with distilled water, the solution was extracted twice with 8 ml of freshly distilled diethyl ether, which, after centrifugation, was transferred to a tube containing 4 ml of 12 N H2SO4. Subsequent to extraction, the ether phase was discarded, the acid was diluted with 4 ml of distilled water, and one drop of 0.1% aqueous bromothymol blue solution was added. Sufficient 10 N NaOH was then used to alkalinize the solution to the blue end point, and, after cooling, it was extracted with 7 ml of freshly distilled diethyl ether. The ether was transferred to a 13 ml centrifuge tube and concentrated to about 20 to 50 /A in water bath maintained at 45 °C. Two to five microlitres of the ether concentrate were injected into the gas chromatograph. The total oxazepam concentration, that is, the unchanged drug plus labile conjugated drug, was determined on separate samples of the biological fluids. The sample (0.5 to 2.0 ml) was diluted with an equal volume of 0.2 M of sodium acetate buffer (pH 5.0) and then incubated at 37 °C overnight with 20 fi\ of Glusulase® (Endo Laboratories, Garden City, New York; 223 991 U/ml of glucuronidase and 62 900 U/ml of sulfatase). The pH of the solution was then adjusted to 7.0 with 5 N NaOH and analyzed by the procedure described for unchanged oxazepam. A Varian gas chromatograph, Model 2100 (Varian Associates, Palo Alto, California), equipped with a tritium electron 422
"trap)
=
Dose .... C r ^ and Vd( '>
=
DoseTVi 0.693 AUCo •
where Cp«>) is the oxazepam plasma concentration at zero time obtained by back extrapolation of the exponential disappearance curve, and AUCo is the total area under the oxazepam plasma concentration/time curve. Statistical differences in the pharmacokinetic parameters between the normal and liver disease groups were analyzed by the two-tailed, nonparametric Mann-Whitney U test, with P «= 0.05 as the minimal level of significance. Results
The plasma concentration/time profile of unchanged and total oxazepam for the young, normal control subjects is shown in Figure 1 and is similar to those previously described (14). Unchanged oxazepam appeared rapidly in the plasma, reaching a maximum level after about 2 to 4 hours in most subjects, after which time the concentration declined monoexponentially. The peak concentration of total oxazepam, achieved at the same time or slightly later, was approximately 150% to 250% greater than unchanged drug, and its concentration also decreased exponentially with a similar half-life to that of the parent drug. Only a small percentage of the administered dose was recovered unchanged in the urine, but more than half of the dose was excreted as conjugated drug. The various mean pharmacokinetic values for oxazepam obtained from the raw data for all of the experimental groups are shown in Table 2. A comparison of the results in the patients with viral hepatitis relative to those in the young control subjects indicated that there were no significant differences in any of the quantitative plasma or urinary oxazepam data (Table 2 ) . Similarly, there were no statistical differences in the data obtained in the older control group and the patients with cirrhosis (Table 2 ) . The cumulative percentage of total oxazepam excreted in the urine, virtually all as glucuronide, for both experimental and control groups is shown in Figure 2. There was a suggestion that both groups of liver-disease patients excreted slightly more conjugated oxazepam into the urine than their respective control groups. This difference, however, did not achieve
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Table 2. Effect of Acute Viral Hepatitis and Cirrhosis in Man on the Disposition and Elimination of Oxazepam (Serax®)
Normal Control, Young Subjects Patients, no. Age, yrs Weight, kg Unchanged! Total Apparent Oral Clearance, ml/min Vd(/j), litres^ Vd(extrap). / * > « §
Urinary excretion, total oxazepam in 48 hours, % of administered dose Urinary excretion, unchanged oxazepam in 48 hours, % of dose Plasma binding, % Blood/plasma ratio
P Value*
Acute Viral Hepatitis
Normal Control, Older Subjects
Cirrhosis
P Value*
8 25.0 ± 2.3 f 74.2 ± 4.0
7 24.5 + 1.8 63.3 ± 3.8
>0.05 0.047
8 53.6 ± 4.5 80.2 ± 5.2
6 46.5 ± 2.7 69.5 ± 5.7
>0.05 >0.05
5.1 ± 0.5 7.1 ± 1.2
5.3 ± 0.3 6.1 ± 0.5
>0.05 >0.05
5.6 + 0.3 6.4 ± 0.4
5.8 ± 0.5 7.8 ± 0.8
>0.05 >0.05
113.5 ± 11.6 47.7 ± 6.3 52.5 ± 5.5
137.4 ± 21.0 51.7 ± 7.0 62.0 ± 8.3
>0.05 >0.05 >0.05
136.0 ± 17.5 61.2 ± 4.6 70.6 ± 4.8
155.5 ± 31.5 60.9 ± 9.5 76.5 ± 12.2
>0.05 >0.05 >0.05
50.60 ± 5.41
63.16 ± 5.68
>0.05
54.95 ± 3.92
61.14 ± 9.14
>0.05
0.23 ± 0.05 86.69 + 1.67 1.04 ± 0.05
0.27 + 0.033 86.03 ± 1.42 0.97 ± 0.02
>0.05 >0.05 >0.05
0.09 + 0.024 89.27 ± 1.59 0.96 ± 0.01
0.18 + 0.05 87.61 + 1.44 0.96 ± 0.02
>0.05 >0.05 >0.05
* Comparison of control versus liver disease group. t Mean ± SE. t See Table 1 for definition. § Vd refers to apparent volume of distribution of drug calculated by two different methods (see Experimental Procedure).
statistical significance at any collection time (Figure 2). Attempts to obtain correlations between the individual half-lives (Table 1) and some of the abnormal liverfunction test values or combinations of these (total bilirubin, serum glutamic oxalacetic transaminase, and serum albumin) were completely unsuccessful. A comparison of the two control groups did not show any major differences in the elimination or plasma binding of oxazepam (P > 0.05), nor were there any discernible correlations between age (14 to 84 years) and such parameters as plasma half-life, urinary excretion of both unchanged and total drug, apparent oral clearance, plasma binding, or the blood/plasma concentration ratio of oxazepam. The older control group had a statistically larger apparent volume of distribution as assessed by Vd(/»> (P < 0.02) than the younger group, but such a difference was not apparent when the distribution space was estimated
aS Vd(extr»p).
In the 2-week study of chronic patients, the peak plasma concentrations of unchanged and total oxazepam after administration of the final dose were between 125% and 175% and 160% and 220%, respectively, of those observed after the initial dose in both the normal subjects and the two patients with cirrhosis, a degree of accumulation consistent with the half-lives and dosage regimen. There were no changes in the elimination half-lives or the ratio of total to unchanged concentrations. Only trivial amounts of total oxazepam (less than 0.1% of the administered dose) were recovered in the bile collected over 48 hours from the two postcholecystectomy patients with biliary T tubes. Discussion
There is little quantitative information concerning the
Figure 2. The effect of acute viral hepatitis and cirrhosis on the urinary excretion of oxazepam. The data for both types of liver disease are expressed as the cumulative recovery of total oxazepam (unchanged plus conjugated) excreted in urine during various time intervals over a 48-hour period, and they are expressed as percentage of administered dose. Also shown is the total 48-hour urinary excretion of unchanged oxazepam. Each bar refers to the mean ± SE of the number of patients and controls indicated. Statistical analysis of the data for each time interval by the non parametric Mann-Whitney U test failed to show a significant difference (P > 0.05). Shull et a/. • Oxazepam in Hepatitis and Cirrhosis
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423
disposition and elimination of oxazepam in man. After oral administration, the drug is rapidly and almost completely absorbed from the gastrointestinal tract, and only about 1% of the dose is excreted unchanged in the urine (18). The remainder of the drug is metabolized, and the glucuronide conjugate is the major metabolite found in the urine. Most investigators report that about 45% to 85% of the dose is excreted in this form in 48 hours (14, 18, 19). It is generally assumed that this metabolism occurs in the liver, although in-vitro animal studies indicate that other organs, particularly the kidney, are capable of conjugating oxazepam but to a much lesser extent than the liver (20). The unavailability of a preparation suitable for intravenous administration has precluded the estimation of the systemic clearance of oxazepam, and the overall elimination processes have usually been characterized by the plasma half-life of the unchanged drug. In normal volunteers, this parameter has generally been found to range from 2.8 to 5.7 hours (14, 19), but some investigators (18, 21) have reported much longer half-lives (11.4 to 21.2 hours). It is not clear whether the latter values are true reflections of drug elimination or whether slow absorption from the oral dosage form distorted the findings. The present data in normal subjects are in good agreement with the lower estimates of previous investigators. The major new finding in this study is the demonstration of unaltered disposition and elimination of oxazepam in patients with acute viral hepatitis and cirrhosis. The lack of any difference in the apparent oral clearance of unchanged oxazepam is particularly important, since this parameter is a* direct measure of the intrinsic ability of the liver to eliminate the drug, assuming that metabolism occurs only in this organ and that all of the administered dose is absorbed (17). The normal rate of urinary excretion of oxazepam glucuronide in patients with liver disease (Figure 2) corroborated the normal plasma elimination pattern in these persons. The urinary oxazepam data differ from prior studies (22) which, using a complex fluorometric method, reported that patients with cirrhosis excreted about two thirds less of the glucuronide than normal subjects but gave no information on drug elimination from plasma. Urinary drug recovery in that study (22), however, was much lower than in other reports (10, 16, 18), and thus the discrepancy may reflect differences in the analytical measurement of oxazepam and its metabolites or the absorption characteristics of the dosage form. The present results are in contrast with those from earlier studies with diazepam, wherein both acute viral hepatitis and cirrhosis caused significant impairment in the elimination of the drug (3). It would appear that the difference is real since two of the patients with cirrhosis had also participated during the past 2 years in similar studies with diazepam (3) and meperidine (23). During this time, these patients had remained clinically stable, and their liver function tests were comparable for each investigation. However, the half-life of diazepam was prolonged 184% and 107% and that of meperidine, 77% and 159%, relative to the mean value in normal subjects, but the comparable values for oxazepam were only 12% and —4%. 424
The reason(s) for this disparity was not specifically investigated, but several observations may bear on this. A possible explanation for the lack of effect of liver disease on the metabolism of oxazepam is that the conjugation occurs to a significant extent in organs other than the liver (20) and that such extrahepatic elimination may compensate for any impairment of hepatic metabolism. Evidence to support this postulate would, however, be most difficult to obtain in man. An attractive alternative hypothesis is that the enzymes responsible for the metabolism of oxazepam are not as functionally impaired in liver disease as those involved in the clearance of diazepam and meperidine. A major and perhaps key difference is the fact that the latter drugs are both predominately metabolized by the mixed function oxygenases, whereas oxazepam metabolism involves conjugation with glucuronic acid. The activity of the glucuronyl transferase involved in the conjugation of bilirubin is also unaltered in acute viral hepatitis and cirrhosis (8). Thus, despite the apparent heterogeneity of these transferases (12), it may well be that the glucuronidation pathway of drug metabolism is less impaired in hepatocellular disease than processes catalyzed by other enzymes. The findings with chloramphenicol (9) support this hypothesis, but further studies involving other drugs and in-vitro studies of conjugation of oxazepam by biopsied liver tissue are clearly required. The clinical implications of our results require cautious interpretation. Benzodiazepines are widely used as sedativetranquilizers and generally have a high margin of safety (24). If such a drug is used acutely in patients with liver disease, it is unlikely that unexpected toxicity will arise, even with impaired elimination of the agent. In a recent study of diazepam given acutely to patients with alcoholic withdrawal, many of whom apparently had liver disease, the drug was well tolerated (25). On the other hand, prolonged administration of sedatives, particularly the related drug chlordiazepoxide (Librium®), has been cited as the second most common precipitant of coma in patients with hepatic dysfunction (2). The accumulation of drug as a result of impaired clearance and prolonged half-life is probably contributory to this situation. There are no published data regarding the effect of liver disease on the elimination of chlordiazepoxide, but the clearance of diazepam is significantly decreased in such persons (3). This suggests that caution should be used when this drug is given over a long period of time to such patients. Careful titration, and perhaps reduction of the dose, to fit the clinical needs of the patient should result in safe and optimal therapy. Based on our pharmacokinetic data, however, oxazepam (when indicated) seems to be a very reasonable oral sedative for patients with liver disease. In our experience it is an effective sedative, it has a relatively short half-life, the major metabolite is pharmacologically inactive, and, most important, unlike diazepam, the drug is eliminated normally in the presence of acute and chronic parenchymal liver disease. Although these studies were carried out with only one dose of the drug, the limited studies of chronic drug use suggest that oxazepam given daily for 2 weeks also does not accumulate more in patients with cirrhosis than in controls. It should be empha-
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sized, however, that patients with liver disease, in addition to potential difficulties in metabolizing sedatives, may also have intrinsic cerebral sensitivity to such agents (25-29). Thus, even with drugs such as oxazepam that are eliminated normally in liver disease, prospective clinical studies will be required to determine the ultimate therapeutic efficacy and safety of these types of agents in the treatment of patients with parenchymal hepatic dysfunction. Interestingly, this study does not show any major difference in oxazepam elimination between the first and second control groups (mean ages, 25 and 54 years, respectively), nor between two young persons (14 and 15 years) and a much older subject (84 years). This is in contrast to previous studies on the elimination of the related benzodiazepine, diazepam, where the half-life increased fourfold to fivefold more than the above age range as a result of increased distribution of the drug (3). Although there were no statistical differences between either the apparent oral clearances and half-lives of the two control age groups, when these parameters were used to calculate an apparent volume of distribution (Vd ( p ) ), the older group seemed to have a slightly higher value than the younger individuals. Such a difference was not observed if the apparent volume of distribution was calculated from the ratio of the administered dose and the drug concentration at zero time obtained by extrapolation of the exponential disappearance curve (Vd extrap ). Since both of these estimates reflect the extent of absorption of the orally administered drug and its distribution, it is impossible to identify the causative mechanism of any observed change. It is clear, however, that even if the difference is truly distributional, the magnitude of any age-dependent phenomenon is far less than that observed for diazepam. Furthermore, the increased sensitivity of elderly patients to the central nervous system activity of the benzodiazepines (30) cannot in the case of oxazepam be attributed to any major alteration in drug disposition, such as its impaired elimination. The greater sensitivity of the elderly person is therefore probably due to alterations in cerebral receptor response. Consequently, pharmacokinetic information is of little value in modifying the oxazepam dosage regimen in these persons. ACKNOWLEDGMENTS: Grant support: by National Institutes of Health grants nos. 5 ROl AAOO267-05 and GM 15431. Received 15 September 1975; revision accepted 22 January 1975. • Requests for reprints should be addressed to Steven Schenker, M.D., Veterans Administration Hospital, 1310 24th Ave. South, Nashville, TN 37203. References 1. SCHENKER S, HOYUMPA AM, WILKINSON GR: The effect of
parenchymal liver disease on the disposition and elimination of sedatives and analgesics. Med Clin North Am 59:887-896, 1975 2. FESSEL JM, CONN HO: An analysis of the causes and prevention of hepatic coma (abstract). Gastroenterology 62:191, 1972 3. KLOTZ U, AVANT GR, HOYUMPA A, et al: The effects of age and
liver disease on the disposition and elimination of diazepam in adult man. / Clin Invest 55:347-359, 1975 4. AYD FJ: Oxazepam update. Dis Nerv Syst 36:1-32, 1975 5. SISENWINE SF, TIO CO, SHRADER SR, et al: The biotransforma-
tion of oxazepam in man, minature swine and rat. Arzneim Forsch 22:632-687, 1972 6. WALKENSTEIN SS, WISER R, GUDMUNDSEN CH, et al: Absorp-
tion, metabolism and excretion of oxazepam and its succinate half-ester. / Pharm Sci 53:1181-1186, 1964 7. AXELROD J, SCHMID R, HAMMAKER L: A biochemical lesion in
congenital, non-obstructive, non-haemolytic jaundice. Nature (Lond) 180:1426-1427, 1957 8. BLACK M, BILLING BH: Hepatic bilirubin UDP-glucuronyl transferase activity in liver disease and Gilbert's syndrome. N Engl J Med 280:1266-1271, 1969 9. KUNIN CM, GLAZKO AJ, FINLAND M: Persistence of antibiotics
in blood of patients with acute renal failure. II. Chloramphenicol and its metabolic products in the blood of patients with severe renal disease or hepatic cirrhosis. J Clin Invest 38:14981508, 1959 10. BARNVILLE HTF, MISK R: Urinary glucuronic acid excretion in liver disease and the effect of a salicylamide load. Br Med J 1:337-340, 1959 11. HAMMAR CH, PRELLWITZ W: The formation of glucuronide after oral administration of acetanilide in patients with chronic hepatitis and liver cirrhosis. Klin Wochenschr 44:1010-1014, 1966 12. DUTTON DJ: Glucuronic Acid. New York, Academic Press, 1966, p. 230 13. SCHWARTZ MA, KOECHLIN RA, POSTMA E, et al: Metabolism
of diazepam in rat, dog, and man. / Pharmacol Exp Ther 149: 423-434, 1965 14. KNOWLES J A, RUELIUS HW: Absorption and excretion of
oxazepam in humans. Determination of the drug by gas-liquid chromatography with electron capture detection. Arzneim Forsch 22:687-692, 1972 15. EVANS GH, NIES AS, SHAND DG: The disposition of propran-
olol. III. Decreased half-life and volume of distribution as a result of plasma binding in man, monkey, dog and rat. / Pharmacol Exp Ther 186:114-122, 1973 16. SADEE W, VAN DER KLEIJN E: Thermolysis of
1,4-benzo-
diazepines during gas chromatography and mass spectroscopy. / Pharm Sci 60:135-137, 1971 17. WILKINSON GR, SHAND DG: A physiological approach to hepatic drug clearance. Clin Pharmacol Ther 18:377-390, 1975 18. VESSMAN J, ALEXANDERSON B, SJOQVIST F, et al: Comparative
pharmacokinetics of oxazepam and nortriptyline after simple oral doses in man, in The Benzodiazepines, edited by GARATTINI S, MUSSINI E, RANDALL LO. New York, Raven Press, 1973, p. 165 19. PELZER H, MASS D: Pharmacokinetics of oxazepam and its hemisuccinate in humans. Arzneim Forsch 19:1652-1656, 1969 20. BERTE F, BENZI G, MANZO L, et al: Investigations on tissue
distribution and metabolism of oxazepam in pregnant guinea pig and rat. Arch Int Pharmacodyn Ther 17:377-381, 1973 21. KAMM G, KELM R: Quantitative analysis of oxazepam in plasma after a single dose and continued application of the drug. Arzneim Forsch 19:1657-1667, 1969 22. STEIDINGER J, SCHMID E: Studies on the metabolism of ox-
azepam. Arzneim Forsch 20:1232-1235, 1970 23. KLOTZ U, MCHORSE TS, WILKINSON GR, et al: The effect of
cirrhosis on the disposition and elimination of meperidine in man. Clin Pharmacol Ther 16:667-675, 1974 24. GREENBLATT DJ, SHADER RI: Benzodiazepines in Clinical Practice. New York, Raven Press, 1974 25. THOMPSON WL, JOHNSON AD, MADDREY WL, et al: Diazepam
and paraldehyde for treatment of severe delirium tremens. A controlled trial. Am Intern Med 82:175-180, 1975 26. MAXWELL TD, CARRELLA M, PARKES JD, et al: Plasma disap-
pearance and cerebral effects of chlorpromazine in cirrhosis. Clin Sci 43:143-151, 1972 27. READ AE, LAIDLAW J, MCCARTHY CF: Effects of chlorpromazine
in patients with hepatic disease. Br Med J 3:497-499, 1969 28. SESSIONS JT, MINKEL HP, BULLARD JC, et al: The effects of
barbiturates in patients with liver disease. / Clin Invest 33: 1116-1127, 1954 29. LAIDLAW J, READ AE, SHERLOCK S:
Morphine tolerance in
hepatic cirrhosis. Gastroenterology 40:389-396, 1961 30. BOSTON COLLABORATIVE SURVEILLANCE PROGRAM: Clinical de-
pression of the central nervous system due to diazepam and chlordiazepoxide in relation to cigarette smoking and age. N Engl J Med 288:277-280, 1973
Shull et a/. • Oxazepam in Hepatitis and Cirrhosis
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Oxazepam (Serax®) is a tranquilizer-sedative of the benzodiazepine group that is predominantly metabolized to a pharmacologically inactive glucuronide and subsequently excreted by way of the kidneys. We administered this drug as a single oral dose to seven patients with acute viral hepatitis, to six with cirrhosis, and to age-matched control subjects. Elimination half-life (jy2) and the apparent oral plasma clearance for the drug in patients with hepatitis and cirrhosis were comparable to values obtained in age-matched controls (P > 0.05). In addition, the apparent volume of distribution of oxazepam, its plasma binding, blood/plasma ratio, and the rate of urinary excretion of oxazepam, predominantly as the glucuronide, were comparable (P > 0.05) in the two groups of patients with liver disease and their respective controls. Unlike many other sedatives, oxazepam is eliminated normally in patients with parenchymal liver disease and therefore, on pharmacokinetic grounds, seems to be an excellent sedative for use in such persons.
PATIENTS with acute and chronic parenchymal liver disease may have impaired elimination of various sedatives and analgesics (1). Moreover, sedatives have been implicated as common precipitants of coma in patients with hepatocellular disease (2). Curiously, little has been published about the disposition and elimination of the benzodiazepines in patients with liver disease, despite their extensive use and significant metabolism by the liver. Recently, it was shown that the clearance of diazepam (Valium®) is reduced by almost half in patients with viral hepatitis and cirrhosis, and this causes a twofold prolongation in the elimination half-life of the drug (3). A systematic evaluation of the other benzodiazepines in patients with liver disease is, however, lacking. The present study assesses the effect of acute and chronic hepatic parenchymal disease on the elimination of oxazepam (Serax®), a benzodiazepine closely related chemically and pharmacologically to diazepam. This drug was chosen for evaluation for several reasons. First, oxazepam is gaining increasing clinical acceptance both in Europe and the U.S. (4). Second, unlike diazepam, it • From the Departments of Medicine (Gastroenterology) and Pharmacology, Vanderbilt University School of Medicine and the Veterans Administration Hospital, Nashville, Tennessee.
420
has been reported to have a relatively short elimination half-life and is predominantly metabolized by conjugation (5, 6) to form a glucuronide that is pharmacologically inactive and is excreted by way of the kidney. The ability of the liver to metabolize various substances by synthesis of their glucuronides has not been well studied in patients with hepatic disease. The formation of bilirubin is impaired in congenital nonhemolytic jaundice ( 7 ) , but this does not seem to be the case in viral hepatitis and cirrhosis ( 8 ) . Furthermore, only 3 of 12 patients with alcoholic cirrhosis had any marked prolongation in the serum half-life of chloramphenicol, and, even in these cases, the urinary recoveries of unchanged and conjugated drug were not different from those obtained in control subjects ( 9 ) . Similarly, patients with cirrhosis challenged with a single dose of salicylamide had no major impairment in the total excretion of glucuronic acid derivatives (10). On the other hand, patients with chronic hepatitis and cirrhosis showed an increase in the urinary excretion of N-acetyl-p-aminophenol but a decreased excretion of its glucuronide after administration of acetanilide (11). Despite this conflict and the heterogeneity of glucuronyl transferase enzymes ( 1 2 ) , it was not unreasonable to postulate that the elimination of oxazepam might not be significantly altered in the presence of liver dysfunction associated with viral hepatitis and cirrhosis. Finally, not only would such a situation have significant clinical importance but it would also permit additional interpretation of the effect of such diseases on the elimination of diazepam, since oxazepam is the terminal and major urinary metabolite of this drug ( 1 3 ) . Experimental Procedure STUDY SUBJECTS
Two experimental groups were studied, consisting of patients with acute viral hepatitis and those with cirrhosis. The group with hepatitis comprised 6 men and 1 woman, 19 to 32 years of age (mean, 24.5 years) and 50 to 80 kg in weight (mean, 63.3 kg). The diagnosis of acute viral hepatitis was based on typical clinical findings and laboratory data. Five of seven patients had a positive blood test for hepatitis B surface antigen (HBsAg) by radioimmunoassay, serum glutamic oxalacetic transaminase (SGOT) level was greater than 600 KU/ ml in all, and bilirubin value was above 5.5 mg/dl in all, with a high of 19 mg/dl. Liver biopsy was thought to be unnecessary to confirm the diagnosis. The group with cirrhosis comprised 6 men, 37 to 57 years of age (mean, 46.5 years) and 55 to 80 kg in weight (mean, 69.5 kg). Cirrhosis was diagnosed Annals of Internal Medicine 84:420-425, 1976
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by typical clinical findings and liver function tests and was confirmed in four of six patients by percutaneous liver biopsy. In the other two patients, who were not biopsied, extensive ascites was present. The cirrhosis was presumed (by history, negative blood HBsAg test, or morphologic data) to be due to alcoholism in all six patients. Of the patients with cirrhosis, four had experienced hepatic encephalopathy previously, two had ascites, two had esophageal varices, one had a portacaval and one a splenorenal shunt, and one was in the early stage of hepatorenal syndrome. With the exception of the last patient, all others with liver dysfunction had normal serum creatinine and blood urea nitrogen levels. All patients with viral hepatitis and four of six with cirrhosis had received no drugs or alcohol for at least 3 weeks before the study. Two patients with cirrhosis were on a diuretic regimen. These and other clinical laboratory features for both experimental groups are shown in Table 1. Since it has been shown that the disposition and elimination of the related drug, diazepam, are age-dependent (3), two separate control groups, age-matched to the hepatitis and cirrhosis groups, respectively, were investigated. The normal controls for the hepatitis patients comprised 7 men and 1 woman, 14 to 30 years of age (mean, 25.0 years) and 56.8 to 90 kg in weight (mean, 74.2 kg). The equivalent controls for the group with cirrhosis comprised 7 men, 45 to 84 years of age (mean, 53.6 years) and 64.0 to 90.0 kg in weight (mean, 80.2 kg). Without the 84-year-old control patient, who was studied to determine the effect of such advanced age on oxazepam metabolism, the mean age is reduced to 49.2 years. Because this man's data agreed with those of the others, it is included in the total control group for the patients with
cirrhosis. All control subjects were free of hepatic and renal dysfunction by clinical and laboratory evaluation, and all had taken no drugs or alcohol for at least 3 weeks before the study. PROTOCOL
After informed consent, oxazepam, 45 mg, was given orally in tablet form (Lot No. 1731963, Wyeth Laboratories, Philadelphia, Pennsylvania) to all persons except the two youngest and the one oldest control subject, who received 15 mg. The purpose of the reduced dosage was to minimize sedation in the oldest control patient, age 84, and to compare oxazepam pharmacokinetics in one elderly and two young normal persons. Prior (14) and present studies have established that the 15 and 45 mg doses are handled comparably by normal persons; hence, the data after normalization were pooled for the two doses. All subjects had fasted overnight before the study, and this state was maintained for the next 5 hours.' Venous blood samples were obtained at 0, 30, 60, 90, and 120 minutes, then every hour for 3 hours, followed by samples every 2 hours for 10 more hours. The blood samples were collected in heparinized tubes, and the plasma was obtained by centrifugation and frozen at - 1 0 °C until analyzed. Urine was collected every 8 hours for 2 days and the samples frozen until analyzed. In two patients with normal liver function who had undergone cholecystectomy, 45 mg of oxazepam were administered orally, and bile was then collected by T tube every 8 hours for 48 hours. Oxazepam, 15 mg, was also administered orally three times a day to two control subjects and two stable subjects with cirrhosis for 2 weeks. Blood samples were collected at the above intervals
Table 1 . Clinical and Hepatic Function Characteristics* of Patients with Acute Viral Hepatitis and Cirrhosis
Patients Age Weight
Plasma Oxazepam TJ UnTotal f changed f
yr kg Acute viral hepatitis 20 67.5 11 2 32 80.5 25 60.0 22 63.0 4t 25 68.2 5t 6 19 54.0 29 50.0 7J§ Cirrhosis 57 55.0 HI
n
h
Total Bilirubin
Alkaline Phosphatase
mg/dl
IU/ml
Serum Plasma AlbuGlutamic min Oxalacetic Transaminase (SGOT) g/dl
Prothrombin Time
Other Drugs
Other Findings
Patient Control
]sec
KU/ml
6.17 5.60 4.29 5.22 5.62 4.03 6.27
5.18 6.27 4.98 8.79 5.30 5.48 6.40
12.0 7.6 5.7 19.0 10.5 5.5 18.5
227 162 200 290 153 190 140
4.4 4.6 4.3 4.0 4.3 4.8 4.5
1390 850 1250 2200 650 1025 1460
10.5 10.2 11.0 9.8 9.8 12.0 13.0
10.4 10.1 11.0 11.0 9.2 11.5 12.0
6.01
7.06
1.0
72
3.7
56
11.2
10.1
2
37
56.0
7.01
7.47
1.4
352
2.7
98
11.7
10.2
311
45
78.0
5.44
6.67
1.9
196
3.6
106
12.8
9.7
4||
49
78.6
6.35
9.17
1.0
90
4.2
20
10.2
10.9
5
48
80.0
6.38
11.01
6.6
347
2.0
165
13.4
10.3
6||
43
56.0
3.80
5.24
1.4
352
2.7
98
11.7
10.2
. .• ... . .. ... ... ... . .. Post portacaval shunt, prior encephalopathy Ascites, prior Lasix* encephalopathy Aldactone* Muscle wasiong, . .. varices, prior encephalopathy Varices, prior . .. encephalopathy Ascites, Aldactone hepatorenal syndrome Postdistal splenorenal shunt . . .
* Normal upper limits for these liver function tests are total bilirubin, 1.0 mg/dl; alkaline phosphatase, 85 IU/ml; SGOT, 40 KU/ml. Lower limit for albumin is 3.5 g/dl. t Unchanged refers to the pharmacologically active parent drug; total refers to the sum of the unchanged oxazepam and oxazepam glucuronide. % Patient's blood positive for hepatitis Bantigen (HBsAg); in the other two persons with viral hepatitis, the test was negative. § Only woman in patient group. || Cirrhosis proved by percutaneous liver biopsy. Shu// et a/. • Oxazepam in Hepatitis and Cirrhosis
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421
capture detector, was used. The column was Pyrex glass (Corning Glass, Corning, New York), 1 m X 2 mm X 6.4 mm packed with 1.5% OV-220 on Gas Chrom Q, 100/120 mesh (Applied Science Laboratory, Inc., State College, Pennsylvania). Operating conditions included an oven temperature of 215 °C; injector temperature, 255 °C; detector oven temperature, 250 °C; and nitrogen flow rate, 30 ml/min. The concentration of oxazepam was obtained by calculating the ratio of the peak height of the drug to that of the internal marker, and then relating this to previously constructed linear calibration curves over the concentration range of 10 to 200 ng/ml. The plasma elimination half-lives (TVi) for unchanged and total oxazepam were determined from the 6- to 24-hour data by linear regression of the logarithm of the plasma concentration and time. The total area under each curve was estimated by the trapezoidal rule, and this permitted calculation of the apparent oral plasma clearance (AUCo) of oxazepam from the ratio of the administered dose to the area under the plasma level/time curve (17). Although the drug was administered orally, two estimates were obtained of oxazepam's apparent volume of distribution (Vd) with the realization that these calculations would be biased by the absorption process. The equations used for this purpose were the following: ... Vd(
Figure 1. Plasma concentration/time profile for unchanged and total oxazepam in the younger normal control group. The data are given as the mean ± SD of eight control subjects, whose mean age is 25 years. The lines were drawn by best visual fit.
after the first dose of Days 1, 7, and 14. The blood/plasma concentration ratio of oxazepam was determined on all of the zero time samples after the addition of drug to give a blood concentration of 40 ng/ml. The plasma binding of oxazepam was estimated by overnight equilibrium dialysis according to the method described by Evans, Nies, and Shand (15) and by using an external buffer concentration of 100 ng/ml. Analysis and Pharmacokinetic Measurements
Unchanged oxazepam in plasma, urine, and bile was determined by gas chromatography of its thermal degradation product (16) and by using electron capture detection. The biological sample (0.5 to 2.0 ml) was added to 2 ml of 1M phosphate buffer (pH 7.0) and 0.1 ml aqueous internal marker solution (Lorazepam®, 0.75 pg/ml). After adjusting the total volume to 8.1 ml with distilled water, the solution was extracted twice with 8 ml of freshly distilled diethyl ether, which, after centrifugation, was transferred to a tube containing 4 ml of 12 N H2SO4. Subsequent to extraction, the ether phase was discarded, the acid was diluted with 4 ml of distilled water, and one drop of 0.1% aqueous bromothymol blue solution was added. Sufficient 10 N NaOH was then used to alkalinize the solution to the blue end point, and, after cooling, it was extracted with 7 ml of freshly distilled diethyl ether. The ether was transferred to a 13 ml centrifuge tube and concentrated to about 20 to 50 /A in water bath maintained at 45 °C. Two to five microlitres of the ether concentrate were injected into the gas chromatograph. The total oxazepam concentration, that is, the unchanged drug plus labile conjugated drug, was determined on separate samples of the biological fluids. The sample (0.5 to 2.0 ml) was diluted with an equal volume of 0.2 M of sodium acetate buffer (pH 5.0) and then incubated at 37 °C overnight with 20 fi\ of Glusulase® (Endo Laboratories, Garden City, New York; 223 991 U/ml of glucuronidase and 62 900 U/ml of sulfatase). The pH of the solution was then adjusted to 7.0 with 5 N NaOH and analyzed by the procedure described for unchanged oxazepam. A Varian gas chromatograph, Model 2100 (Varian Associates, Palo Alto, California), equipped with a tritium electron 422
"trap)
=
Dose .... C r ^ and Vd( '>
=
DoseTVi 0.693 AUCo •
where Cp«>) is the oxazepam plasma concentration at zero time obtained by back extrapolation of the exponential disappearance curve, and AUCo is the total area under the oxazepam plasma concentration/time curve. Statistical differences in the pharmacokinetic parameters between the normal and liver disease groups were analyzed by the two-tailed, nonparametric Mann-Whitney U test, with P «= 0.05 as the minimal level of significance. Results
The plasma concentration/time profile of unchanged and total oxazepam for the young, normal control subjects is shown in Figure 1 and is similar to those previously described (14). Unchanged oxazepam appeared rapidly in the plasma, reaching a maximum level after about 2 to 4 hours in most subjects, after which time the concentration declined monoexponentially. The peak concentration of total oxazepam, achieved at the same time or slightly later, was approximately 150% to 250% greater than unchanged drug, and its concentration also decreased exponentially with a similar half-life to that of the parent drug. Only a small percentage of the administered dose was recovered unchanged in the urine, but more than half of the dose was excreted as conjugated drug. The various mean pharmacokinetic values for oxazepam obtained from the raw data for all of the experimental groups are shown in Table 2. A comparison of the results in the patients with viral hepatitis relative to those in the young control subjects indicated that there were no significant differences in any of the quantitative plasma or urinary oxazepam data (Table 2 ) . Similarly, there were no statistical differences in the data obtained in the older control group and the patients with cirrhosis (Table 2 ) . The cumulative percentage of total oxazepam excreted in the urine, virtually all as glucuronide, for both experimental and control groups is shown in Figure 2. There was a suggestion that both groups of liver-disease patients excreted slightly more conjugated oxazepam into the urine than their respective control groups. This difference, however, did not achieve
April 1976 • Annals of Internal Medicine • Volume 84 • Number 4
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Table 2. Effect of Acute Viral Hepatitis and Cirrhosis in Man on the Disposition and Elimination of Oxazepam (Serax®)
Normal Control, Young Subjects Patients, no. Age, yrs Weight, kg Unchanged! Total Apparent Oral Clearance, ml/min Vd(/j), litres^ Vd(extrap). / * > « §
Urinary excretion, total oxazepam in 48 hours, % of administered dose Urinary excretion, unchanged oxazepam in 48 hours, % of dose Plasma binding, % Blood/plasma ratio
P Value*
Acute Viral Hepatitis
Normal Control, Older Subjects
Cirrhosis
P Value*
8 25.0 ± 2.3 f 74.2 ± 4.0
7 24.5 + 1.8 63.3 ± 3.8
>0.05 0.047
8 53.6 ± 4.5 80.2 ± 5.2
6 46.5 ± 2.7 69.5 ± 5.7
>0.05 >0.05
5.1 ± 0.5 7.1 ± 1.2
5.3 ± 0.3 6.1 ± 0.5
>0.05 >0.05
5.6 + 0.3 6.4 ± 0.4
5.8 ± 0.5 7.8 ± 0.8
>0.05 >0.05
113.5 ± 11.6 47.7 ± 6.3 52.5 ± 5.5
137.4 ± 21.0 51.7 ± 7.0 62.0 ± 8.3
>0.05 >0.05 >0.05
136.0 ± 17.5 61.2 ± 4.6 70.6 ± 4.8
155.5 ± 31.5 60.9 ± 9.5 76.5 ± 12.2
>0.05 >0.05 >0.05
50.60 ± 5.41
63.16 ± 5.68
>0.05
54.95 ± 3.92
61.14 ± 9.14
>0.05
0.23 ± 0.05 86.69 + 1.67 1.04 ± 0.05
0.27 + 0.033 86.03 ± 1.42 0.97 ± 0.02
>0.05 >0.05 >0.05
0.09 + 0.024 89.27 ± 1.59 0.96 ± 0.01
0.18 + 0.05 87.61 + 1.44 0.96 ± 0.02
>0.05 >0.05 >0.05
* Comparison of control versus liver disease group. t Mean ± SE. t See Table 1 for definition. § Vd refers to apparent volume of distribution of drug calculated by two different methods (see Experimental Procedure).
statistical significance at any collection time (Figure 2). Attempts to obtain correlations between the individual half-lives (Table 1) and some of the abnormal liverfunction test values or combinations of these (total bilirubin, serum glutamic oxalacetic transaminase, and serum albumin) were completely unsuccessful. A comparison of the two control groups did not show any major differences in the elimination or plasma binding of oxazepam (P > 0.05), nor were there any discernible correlations between age (14 to 84 years) and such parameters as plasma half-life, urinary excretion of both unchanged and total drug, apparent oral clearance, plasma binding, or the blood/plasma concentration ratio of oxazepam. The older control group had a statistically larger apparent volume of distribution as assessed by Vd(/»> (P < 0.02) than the younger group, but such a difference was not apparent when the distribution space was estimated
aS Vd(extr»p).
In the 2-week study of chronic patients, the peak plasma concentrations of unchanged and total oxazepam after administration of the final dose were between 125% and 175% and 160% and 220%, respectively, of those observed after the initial dose in both the normal subjects and the two patients with cirrhosis, a degree of accumulation consistent with the half-lives and dosage regimen. There were no changes in the elimination half-lives or the ratio of total to unchanged concentrations. Only trivial amounts of total oxazepam (less than 0.1% of the administered dose) were recovered in the bile collected over 48 hours from the two postcholecystectomy patients with biliary T tubes. Discussion
There is little quantitative information concerning the
Figure 2. The effect of acute viral hepatitis and cirrhosis on the urinary excretion of oxazepam. The data for both types of liver disease are expressed as the cumulative recovery of total oxazepam (unchanged plus conjugated) excreted in urine during various time intervals over a 48-hour period, and they are expressed as percentage of administered dose. Also shown is the total 48-hour urinary excretion of unchanged oxazepam. Each bar refers to the mean ± SE of the number of patients and controls indicated. Statistical analysis of the data for each time interval by the non parametric Mann-Whitney U test failed to show a significant difference (P > 0.05). Shull et a/. • Oxazepam in Hepatitis and Cirrhosis
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423
disposition and elimination of oxazepam in man. After oral administration, the drug is rapidly and almost completely absorbed from the gastrointestinal tract, and only about 1% of the dose is excreted unchanged in the urine (18). The remainder of the drug is metabolized, and the glucuronide conjugate is the major metabolite found in the urine. Most investigators report that about 45% to 85% of the dose is excreted in this form in 48 hours (14, 18, 19). It is generally assumed that this metabolism occurs in the liver, although in-vitro animal studies indicate that other organs, particularly the kidney, are capable of conjugating oxazepam but to a much lesser extent than the liver (20). The unavailability of a preparation suitable for intravenous administration has precluded the estimation of the systemic clearance of oxazepam, and the overall elimination processes have usually been characterized by the plasma half-life of the unchanged drug. In normal volunteers, this parameter has generally been found to range from 2.8 to 5.7 hours (14, 19), but some investigators (18, 21) have reported much longer half-lives (11.4 to 21.2 hours). It is not clear whether the latter values are true reflections of drug elimination or whether slow absorption from the oral dosage form distorted the findings. The present data in normal subjects are in good agreement with the lower estimates of previous investigators. The major new finding in this study is the demonstration of unaltered disposition and elimination of oxazepam in patients with acute viral hepatitis and cirrhosis. The lack of any difference in the apparent oral clearance of unchanged oxazepam is particularly important, since this parameter is a* direct measure of the intrinsic ability of the liver to eliminate the drug, assuming that metabolism occurs only in this organ and that all of the administered dose is absorbed (17). The normal rate of urinary excretion of oxazepam glucuronide in patients with liver disease (Figure 2) corroborated the normal plasma elimination pattern in these persons. The urinary oxazepam data differ from prior studies (22) which, using a complex fluorometric method, reported that patients with cirrhosis excreted about two thirds less of the glucuronide than normal subjects but gave no information on drug elimination from plasma. Urinary drug recovery in that study (22), however, was much lower than in other reports (10, 16, 18), and thus the discrepancy may reflect differences in the analytical measurement of oxazepam and its metabolites or the absorption characteristics of the dosage form. The present results are in contrast with those from earlier studies with diazepam, wherein both acute viral hepatitis and cirrhosis caused significant impairment in the elimination of the drug (3). It would appear that the difference is real since two of the patients with cirrhosis had also participated during the past 2 years in similar studies with diazepam (3) and meperidine (23). During this time, these patients had remained clinically stable, and their liver function tests were comparable for each investigation. However, the half-life of diazepam was prolonged 184% and 107% and that of meperidine, 77% and 159%, relative to the mean value in normal subjects, but the comparable values for oxazepam were only 12% and —4%. 424
The reason(s) for this disparity was not specifically investigated, but several observations may bear on this. A possible explanation for the lack of effect of liver disease on the metabolism of oxazepam is that the conjugation occurs to a significant extent in organs other than the liver (20) and that such extrahepatic elimination may compensate for any impairment of hepatic metabolism. Evidence to support this postulate would, however, be most difficult to obtain in man. An attractive alternative hypothesis is that the enzymes responsible for the metabolism of oxazepam are not as functionally impaired in liver disease as those involved in the clearance of diazepam and meperidine. A major and perhaps key difference is the fact that the latter drugs are both predominately metabolized by the mixed function oxygenases, whereas oxazepam metabolism involves conjugation with glucuronic acid. The activity of the glucuronyl transferase involved in the conjugation of bilirubin is also unaltered in acute viral hepatitis and cirrhosis (8). Thus, despite the apparent heterogeneity of these transferases (12), it may well be that the glucuronidation pathway of drug metabolism is less impaired in hepatocellular disease than processes catalyzed by other enzymes. The findings with chloramphenicol (9) support this hypothesis, but further studies involving other drugs and in-vitro studies of conjugation of oxazepam by biopsied liver tissue are clearly required. The clinical implications of our results require cautious interpretation. Benzodiazepines are widely used as sedativetranquilizers and generally have a high margin of safety (24). If such a drug is used acutely in patients with liver disease, it is unlikely that unexpected toxicity will arise, even with impaired elimination of the agent. In a recent study of diazepam given acutely to patients with alcoholic withdrawal, many of whom apparently had liver disease, the drug was well tolerated (25). On the other hand, prolonged administration of sedatives, particularly the related drug chlordiazepoxide (Librium®), has been cited as the second most common precipitant of coma in patients with hepatic dysfunction (2). The accumulation of drug as a result of impaired clearance and prolonged half-life is probably contributory to this situation. There are no published data regarding the effect of liver disease on the elimination of chlordiazepoxide, but the clearance of diazepam is significantly decreased in such persons (3). This suggests that caution should be used when this drug is given over a long period of time to such patients. Careful titration, and perhaps reduction of the dose, to fit the clinical needs of the patient should result in safe and optimal therapy. Based on our pharmacokinetic data, however, oxazepam (when indicated) seems to be a very reasonable oral sedative for patients with liver disease. In our experience it is an effective sedative, it has a relatively short half-life, the major metabolite is pharmacologically inactive, and, most important, unlike diazepam, the drug is eliminated normally in the presence of acute and chronic parenchymal liver disease. Although these studies were carried out with only one dose of the drug, the limited studies of chronic drug use suggest that oxazepam given daily for 2 weeks also does not accumulate more in patients with cirrhosis than in controls. It should be empha-
April 1976 • Annals of Internal Medicine • Volume 84 • Number 4
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sized, however, that patients with liver disease, in addition to potential difficulties in metabolizing sedatives, may also have intrinsic cerebral sensitivity to such agents (25-29). Thus, even with drugs such as oxazepam that are eliminated normally in liver disease, prospective clinical studies will be required to determine the ultimate therapeutic efficacy and safety of these types of agents in the treatment of patients with parenchymal hepatic dysfunction. Interestingly, this study does not show any major difference in oxazepam elimination between the first and second control groups (mean ages, 25 and 54 years, respectively), nor between two young persons (14 and 15 years) and a much older subject (84 years). This is in contrast to previous studies on the elimination of the related benzodiazepine, diazepam, where the half-life increased fourfold to fivefold more than the above age range as a result of increased distribution of the drug (3). Although there were no statistical differences between either the apparent oral clearances and half-lives of the two control age groups, when these parameters were used to calculate an apparent volume of distribution (Vd ( p ) ), the older group seemed to have a slightly higher value than the younger individuals. Such a difference was not observed if the apparent volume of distribution was calculated from the ratio of the administered dose and the drug concentration at zero time obtained by extrapolation of the exponential disappearance curve (Vd extrap ). Since both of these estimates reflect the extent of absorption of the orally administered drug and its distribution, it is impossible to identify the causative mechanism of any observed change. It is clear, however, that even if the difference is truly distributional, the magnitude of any age-dependent phenomenon is far less than that observed for diazepam. Furthermore, the increased sensitivity of elderly patients to the central nervous system activity of the benzodiazepines (30) cannot in the case of oxazepam be attributed to any major alteration in drug disposition, such as its impaired elimination. The greater sensitivity of the elderly person is therefore probably due to alterations in cerebral receptor response. Consequently, pharmacokinetic information is of little value in modifying the oxazepam dosage regimen in these persons. ACKNOWLEDGMENTS: Grant support: by National Institutes of Health grants nos. 5 ROl AAOO267-05 and GM 15431. Received 15 September 1975; revision accepted 22 January 1975. • Requests for reprints should be addressed to Steven Schenker, M.D., Veterans Administration Hospital, 1310 24th Ave. South, Nashville, TN 37203. References 1. SCHENKER S, HOYUMPA AM, WILKINSON GR: The effect of
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Shull et a/. • Oxazepam in Hepatitis and Cirrhosis
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