Influence of congestive heart failure on blood levels of lidocaine and its active monodeethylated metabolite The blood concentrations of lidocaine and its active monodeethylated metabolite, monoethylglycinexylidide (M EG X), were measured in 31 patients who were receiving infusions of lidocaine intravenously. In 3 patients who were studied intensively, the elimination half-life of MEGX was 120 min, which was similar to the elimination half-life of lidocaine (139 min). An additional 3 patients demonstrated a higher ratio of the concentration in blood of MEGX to lidocaine, and the MEGX may have contributed, in 1 patient, to the central nervous system toxicity that occurred during the infusion. Elevated concentrations of MEGX in blood were associated with congestive heart failure (r = 0.5, p = 0.004). Our data suggest that the elimination of MEGX may be decreased in patients with depressed cardiac output and sympathomimetic compensation.
Hillel Halkin, M.D., * Peter Meffin, Ph. D., Kenneth L. Melmon, M.D., and Malcolm Rowland, Ph.D. San Francisco, Calif. Division of Clinical Pharmacoiogy, the Departments of Medicine and Pharmacology, School of Medicine, the Department of Pharmacy, School of Pharmacy, and the Cardiovascular Research Institute, University of California, San Francisco
The disposition kinetics and metabolism of lidocaine have been the subject of many recent investigations. 3 , 5, 7 Monoethylglycinexylidide (MEGX), the metabolite that arises from the N-deethylation of lidocaine, has been shown to share some of the pharmacologic properties of Supported in part by the Bay Area Heart Association and by National Institutes of Health Grants Nos. GM 16496, GM 0000 I. and GM 01791. Received for publication Nov. 2, 1974. Accepted for publication March 17. 1975. Reprint requests to: M. Rowland. Ph.D., Department of Pharmacy, University of California, San Francisco, San Francisco, Calif. 94143. • Merck International Fellow in Clinical Pharmacology; current address: Department of Medicine, Sheba Medical Center. Tel Hashomer. Israel.
the parent compound. 2 , 8 Previous studies have suggested that, in some patients, accumulation of MEGX during the course of the administration of lidocaine may contribute to the occurrence of the signs and symptoms of central nervous system toxicity that previously were attributed to the drug itself.9, 10 The concentrations of lidocaine and MEGX were measured in the blood of 31 patients who were receiving lidocaine infusions for the prevention or treatment of cardiac arrhythmias. Aspects of the pharmacokinetics of the metabolite were analyzed in a subgroup of the 31 patients; clinical correlates for the concentrations of MEGX in blood were sought for the entire group. 669
670
Clinical Pharmacology and Therapeutics
Halkin et al.
Materials and methods
We attempted to obtain reasonable estimates of the plateau levels of both lidocaine and MEGX by taking single samples of blood as late as possible after the attending physician had commenced lidocaine infusions. In most cases this was at least 10 hr after the initiation of lidocaine therapy. We did not interfere with or try to influence the manner in which lidocaine was given. A detailed history of lidocaine dosing (boluses and rates of infusion) was recorded for each patient by the nursing staff. Clinical data relating to history, physical findings, and laboratory results were obtained from the patients' charts, with particular emphasis on the presence or absence of signs and symptoms of congestive heart failure (peripheral edema, pulmonary congestion, elevated jugular venous pressure, gallop rhythm). In 3 of the 31 patients the lidocaine hydrochloride infusion rate was controlled with the use of a Harvard pump, at a rate of 2.5 mg/min; 20 samples of blood were obtained over the II-hr course of the infusion and after its discontinuation. Chemical analysis. The concentrations of lidocaine in blood were determined by the use of gas chromatography. 7 The concentrations of MEGX in blood were determined by a specific gas chromatographic method: A Varian series 1200 gas chromatograph fitted with a nickel-63 electron-capture detector was used for the analysis. Glass columns, 1.8 m, 0.3 cm o.d., packed with 3% OV-17 on Gas-Chrom-Q, 100120 mesh, were used. The carrier gas (5% methane in argon) had a flow rate of 20 ml/ min. The oven was maintained at 235 C, the injector port at 250 0 C, and the detector at 3200 C. The following were added to a 10 ml screwtopped tube: 0.05 to I ml of whole blood or plasma containing 10 to 100 ng of MEGX, together with internal standard solution (50 ng in 100 ILl of water), lOO J.LI of 2N NaOH and 3 ml of analytical reagent grade pentyl acetate. The internal standard was 3' -methoxy-2-ethylamino acetanilide hydrochloride (mp, 149 0 to 1500 C). The tube was then fitted with a Teflonlined screw- top and the contents were mixed vigorously for 2 min. After mixing, the tube was centrifuged and approximately 2.5 ml of 0
the pentyl acetate were transferred to a second 10-ml tube that had a tapered portion at the base of about 200 ILl capacity. To the second tube were added lOO ILl of 0.1 N H 2S04 , and the contents were then centrifuged. The pentyl acetate was removed and discarded. An additional 1 ml of pentyl acetate was added to the tube and was then mixed and centrifuged and the pentyl acetate discarded. Sodium hydroxide (20 ILl; 2 N) and 100 ILl of pentyl acetate were added to the H2 S04 solution that remained in the base of the tube. The tube contents were then mixed and centrifuged as described previously. Pentafluorobenzoyl chloride, * 20J.LI, of a freshly prepared 0.2% solution in benzene, was added to the pentyl acetate phase and the tube was allowed to sit at room temperature for 2 to 3 min. The contents of the tube were again mixed and centrifuged as described previously and 0.5 to I ILl of the pentyl acetate was injected into the gas chromatograph. The following modifications were made on samples containing amounts of MEGX greater than 100 ng, which enabled measurements of MEGX in the range of 100 to 1,000 ng. In the initial step of the extraction the amount of internal standard added was increased to 500 ng and the extraction was carried out as described previously. The final extraction was made with 200 J.LI of pentyl acetate and the derivatization was carried out with 20 ILl of 1.0% solution of pentafluorobenzoyl chloride in benzene. Only 0.1 to 0.5 J.LI of the pentyl acetate was injected into the chromatograph. Under the chromatographic conditions described previously, the peaks that resulted from MEGX and the internal standard had retention times of 3.3 and 4.7 min, respectively. Calibration curves were prepared by adding known amounts of MEGX to blood or plasma, which were then taken through the assay procedure. The plot of the peak height ratio of the derivative of MEGX to that of the internal standard vs the amount of MEGX added was linear over the two ranges examined (10 to 100 ng and 100 to 1,000 ng). Such a calibration curve is shown for the range 10 to 100 ng in • Pentafluorobenzoyl chloride was supplied by Pierce Chemical Co., Rockford, Ill.
Lidocaine and metabolite levels
Volume 17 Number 6
~~~
UDOCA~E
,....
:·"i·-e.!--·--·-.·-..:.·--=----.
~ 05~ ~
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• •
I 8
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.' \'.
MEGX
• __e
671
2
4
6
8
12
10
14
~ HRS
INFUSION (33)Jg/Kg/min)
Fig. 1. Observed (e) blood concentrations and fitted curves (-) of lidocaine and MEGX in 2 patients receiving a bolus and constant infusion of lidocaine.
Table I. Calibration curve for MEGX from blood
MEGX added to blood (ng)
Peak height ratio MEGX: Internal standard
Peak height ratio MEGX: Internal standard
ng MEGX
0.380 0.676 1.07 2.77 3.50
10
20
30 80
100
0.038 0.034 0.036 0.035 0.035
The data were fitted to the regression equation. y = 0.0347x
+ 0.0129. r
= 0.99985.
Table I. Calibration curves prepared from water, plasma, or whole blood did not differ significantly. No interfering peaks were observed when plasma or blood obtained from patients who had not received lidocaine was taken through the assay procedure. The precision of the method was determined by replicate assays of 5 samples that contained 30 ng of MEGX. The per cent relative standard deviation of the mean was 0.882%. No contribution of lidocaine to the MEGX assay, nor of MEGX to the lidocaine assay, was observed when control plasma samples were spiked with known quantities of these compounds. Results
The blood concentration-time curves for lidocaine and MEGX in 2 of the patients re-
ceiving infusions at a rate of 2.5 mg/min are shown in Fig. I. The lidocaine and MEGX data were fitted to the model depicted in Fig. 2 with the use of the program NONLIN. * Each datum was weighted by the reciprocal of the square of its value. Estimates of the various pharmacokinetic parameters and the steadystate blood concentrations of lidocaine and MEGX are listed in Table 11. Clinical data, average dosing rates (calculated by dividing the total amount administered by the infusion period), and individual patient blood concentrations of lidocaine and MEGX for all patients are listed in Table Ill. Also listed are the concentrations, which are normalized to a 10 mcg/ ruin/kg infusion rate. * Metzler. zoo. Mich.
c.:
Statistics Department. the Upjohn Co .. Kalama-
Halkin et al.
672
Clinical Pharmacology and Therapeutics
Table II. Derived pharmacokinetic parameters for lidocaine and MEGX Lidocaine
Subject
Infusion rate (mglmin)
28 29 30
2.5 2.5 2.5
Distribution
(min)
TV2
Volume of distribution (l/kg)
Steadystate concentration (mcglml)
Clearance (ml/minlkg)
87 (23) 165 (75) 163 (50)
1.04 2.5 0.92
2.5 1.9 4.1
13.6 18.0 8.0
Elimination
TV2 (min)
10.2 (34)* 21.8 (27) 10.6 (34)
* Coefficient of variation. t
2
= I _
r
sum of sguared deviations corrected sum of squared deviations'
Table Ill. Clinical information and blood concentrations of lidocaine and MEGX
Patient
Age
Sex
1 2 3 4 5* 6 7 8 9 10
65 61 43 54 54 50 52
M M F F F F F F M M M M M M M M M M M M M M M M M M M M M M M
11
12 13 14 15 16 17
18 19 20 21* 22 23 24 25 26 27
28 29 30 31
64
65 51 55 55 55 55 55 51 55 58 56 76 68 77
45 36 55 69 53 43 52 70 68
* Patient experienced
Heart failure
0 0 0
+ + + + 0 0 0 0
+ 0 0 0 0 0
+ 0
+ + 0 0 0 0 0 0 0 0 0 0
Duration of lidocaine infusion (hr)
Rate of lidocaine infusion (mcglminlkg)
Blood concentration of lidocaine (mcglml)
Blood concentration of MEGX (mcglml)
12 8 8.5 18.5 15 6.5 5 10 12.5 20 5 16 15 27 14 23.5 52
6.2 143.3 47 107 65 27.5 47.1 65.6 54 21.5 16.5 31 46.5 28 55 50 67 47 49 35 18.5 24 28 24 23 38 30 34 35 33 33
1.7 7.6 2.4 7.4 9.8 2.3 8.1 3.1 1.8 0.4 1.7 4.9 2.5 3.9 2.3 3.3 21.7 3.2 3.2 1.8 3.5 2.2 6.2 2.7 3.4 10.6 7 2.5 1.9 4.1 6.3
0.2 0.5 0.45 0.7 0.6 0.4 0.7 0.5 0.2 0.35 0.2 1.4 0.5 0.4 0.6 0.1 0.5 2.5 0.3 0.9 4.2 0.3 0.8 0.3 0.35 1.4
72
48 27 48 37 11 11
11 11.5 11 11 11 11 11
central nervous system toxicity during lidocaine infusion.
1.2
0.5 0.6 0.9 0.75
Volume 17 Number 6
Lidocaine and metabolite levels
MEGX
(min)
Steadystate concentration (mcglml)
r2t
199 (29) 71 (13) 87 (56)
0.5 0.6 1.9
0.978 0.992 0.975
Distribution Ph (min)
Elimination
6.1 (24) 4 (60) 48 (63)
TV2
673
Separation of the patients on the basis of the presence or absence of congestive heart failure at the time of the lidocaine infusion allowed a comparison of the blood concentrations of lidocaine and MEGX in the two groups, as seen in Table IV. Partial correlation analysis 6 (Table V) revealed a significant positive correlation between the presence of congestive heart failure and MEGX levels in this group of patients. Lidocaine infusion rates and blood concentrations tended to be higher in the heart failure group, although this did not attain statistical significance. Discussion
Blood concentration of lidocaine 110 mcg Imin Ikg infusion rate
Blood concentration of MEGX/JO mcglminlkg infusion rate
2.7 0.53 0.5 0.7
0.32 0.035 0.096 0.065 0.092 0.15 0.15 0.076 0.037 0.16 0.12 0.47 0.11 0.14
1.5
0.84 1.7 0.47 0.33 0.19 1.0 1.5 0.54 1.4 0.42 0.66 3.2 0.68 0.65 0.52 1.9 0.92 2.2 1.1
1.5 2.8 2.3 0.74 0.54 0.12 0.19
Mean 1.1
0.11
0.020 0.075 0.53 0.061 0.26 2.27 0.13 0.29 0.13 0.15 0.37 0.40 0.15 0.17 0.27 0.23 0.245
The pharmacokinetic parameters for lidocaine derived for the 3 patients studied intensively are not significantly different from those found in normal volunteers. 7 In these 3 subjects, estimates of the distribution half-life and elimination half-life of MEGX were found to range between 4 and 48 min and 71 and 199 min, respectively (Table Ill). These data are insufficient for defining population estimates, but the elimination half-life of MEGX estimated by others! falls within the range we found. The lack of clearance value for MEGX (which can be defined only by independent administration of the metabolite), and the uncertainty of knowing whether a fraction of the formed MEGX is further metabolized in the liver and is not seen systemically, prevents an estimate of the fraction of the dose of lidocaine actually being metabolized via MEGX. Although the model chosen failed to fit the early MEGX levels, it was felt adequate to describe the overall disposition kinetics of lidocaine and MEGX. On average, the concentration achieved per 10 mcg/min/kg infusion rate is 1.1 mcg/ml (Table Ill), which agrees with that noted previously.4. 7 The variability is probably caused by the relative inconstancy of the infusion rate, the failure of all patients to be at steady state, and the diverse clinical status of the patients. MEGX levels generally were only one fourth of those of lidocaine. Other investigators suggest9 • !O that in some
674
Clinical Pharmacology and Therapeutics
Halkin et al.
Table IV. Influence of heart failure on MEGX and lidocaine blood concentrations
Heart failure *
Age (yr)
Rate of lidocaine infusion (mcglminlkg)
Duration of lidocaine infusion (hr)
Present (n = 8)
58,4 ± 3.2t
47.3 ± 9.9
26 ± 8
Absent (n = 23)
58.5 ± 2
41.4 ± 5.6
17.5 ± 2.6
Blood concentration of lidocaine (mcglml)
Blood concentration of MEGX (mcglml)
5.1 ± 1
1,4 ± 0,46 (p = 0.003)
4,4 ± 0.9
0.5 ± 0.1 (p = 0.003)
* As judged by the presence of two or more of the following: edema. pulmonary vascular congestion, elevated jugular venous pressure. gallop rhythm, tMean ± SEM.
Table V. Multivariate partial correlation analysis of MEGX and lidocaine blood concentrations Heart failure *
Infusion ratet
Infusion durationt
Lidocaine Concentration
NS
r = 0.33 p = 0.04
NS
MEGX Concentration
r = 0.5 p = 0.004
NS
r = 0.3 P = 0.062
* Controlling for
age, sex, duration, and rate of infusion.
t Controlling for age. sex. heart failure presence. and duration of infusion. tControlling for age, sex, he an failure presence, and infusion rate.
Lidocaine
Bolus + Infusion
•
n
I
}
Lidocaine
Disposition
I
MEGX
Disposition
Fig. 2. Model used to describe the pharmacokinetics of lidocaine and MEGX.
patients recelVlng lidocaine appreciable amounts of active metabolite may accumulate and contribute to the pharmacologic effects, both beneficial and toxic, that are seen clinically. Our results confirm and extend this suggestion. Three of the patients listed in Table III (Patients 19, 2l, 22) had MEGX blood con-
centrations similar to those of lidocaine, Studies in experimental animals have demonstrated the near equipotence of lidocaine and MEGX in producing convulsions. 2 , 8 Two patients in this series manifested signs of lidocaine toxicity (paresthesia and marked confusion) during the course of the lidocaine infusions. In one (Patient 5), these signs and symptoms of toxicity occurred 7 hr after the start of the infusion and lasted 2 hr after the infusion rate was diminished. In the other (Patient 21), the symptoms occurred 8 hr after the start of the infusion and lasted 1.5 hr after the infusion rate was dropped. The lack of neurologic sequelae and of any other clinical occurrence or pharmacologic intervention at the time of the appearance of this symptom-complex suggests its relation to lidocaine infusion. The amelioration of the clinical signs after the decrease in the infusion rate supports this contention. In Patient 5, the toxicity could be explained by the lidocaine blood concentration alone (9.8 mcg/ml), but in Patient 21 the MEGX concentration
Lidocaine and metabolite levels
Volume 17 Number 6
probably contributed to the reaction (lidocaine 3.5 mcg/ml, MEGX 4.2 mcg/ml), although the contribution of other metabolites of lidocaine cannot be discounted. Of the 31 patients studied, 22 had lidocaine levels below 5 mcg/ml, and 27 had levels below 8 mcg/ml. Four had higher levels, one of whom (Patient 5) manifested toxicity. Toxicity is usually anticipated above 8 mcg/mI4; however given the high variability frequently seen in the responsiveness of individuals to drugs, we hesitate to draw any conclusions from our data regarding the relative safety of higher concentrations of lidocaine. Table IV shows an analysis of the blood level data for lidocaine and MEGX in the 31 patients and is based on the presence or absence of congestive heart failure. No difference was found between the two groups with respect to age, duration of the infusion of lidocaine, or lidocaine concentrations, although MEGX levels were significantly higher in the heart failure group. Multivariate partial correlation analysis (Table V) revealed a significant positive correlation between lidocaine concentrations and the lidocaine infusion rates, but no correlation between lidocaine levels and the presence of heart failure. The absence of this correlation is not in conflict with previous reportsll' 12; it was probably obscured in our patients by the variable dosages and by the varying degrees of congestive heart failure that were assessed at the bedside and the relative inconstancy in the rates of lidocaine infusion. Nevertheless, MEGX blood concentrations were significantly higher when heart failure was present. This correlation maintained its significance even after the patient's age, sex, and the duration and rate of the lidocaine infusion had been taken into account. Conditions of hemodynamic instability, and congestive heart failure in particular, have been shown to reduce the volume of distribution and plasma clearance of lidocaine. 1!' 12 Our data indicate that a similar influence may be exerted by these conditions upon elimination of MEGX, which is normally further metabolized in the liver. 10 Thus congestive heart failure, in addition to causing inappropriately high lidocaine levels for any given rate of lidocaine
675
infusion, may further complicate the therapeutic setting by causing excessive accumulation of the active metabolite. It may be that the elimination of MEGX is also influenced by hepatic blood flow. The reason that a higher MEGX/lidocaine ratio is not seen in all patients with heart failure may be due to changes in the fraction of lidocaine that is metabolized via MEGX. This possibility can be explored only by direct administration of the metabolite. A final practical consideration is that the halflife of MEGX is similar to that of lidocaine. Interruption of the lidocaine infusion should therefore usually result in a relatively rapid decline in the blood levels of both compounds, and prolonged presence of this metabolite in the circulation probably occurs only in those instances in which the elimination of lidocaine is markedly slowed. The authors are grateful to Astra Pharmaceutical Products, Inc., Worcester, Mass., for kindly providing a sample of MEGX.
References I. Adjepon-Yamoah, K. K., and Prescott, L. F.:
2.
3.
4.
5.
6.
7.
8.
Lignocaine metabolism in man, Br. l. Pharmacol. 47:672-673, 1973. Blumer, l., Strong, l. M., and Atkinson, A. l., lr.: The convulsant potency of lidocaine and its N-dealkylated metabolites, In press, l. Pharmacol. Exp. Ther. 186:31-36, 1973. Boyes, R. N., Scott, D. B., lebson, P. l., Goodman, M. 1., and lulian, D. G.: Pharmacokinetics of lidocaine in man, CUN. PHARMACOL. THER. 12: 105-116, 1971. Gianelly, R., Von der Groeben, l. 0., Spivack, A. P., and Harrison, D. c.: Effect of lidocaine on ventricular arrhythmia in patients with coronary heart disease, N. Engl. l. Med. 277: 1215-1219, 1967. Keenaghan, l. B., and Boyes, R. N.: The tissue distribution, metabolism and excretion of lidocaine in rats, guinea pigs, dogs and man, l. Pharmacol. Exp. Ther. 180:454-463, 1972. Nie, N. H., Bent, D. H., and Hull, C. H., editors: Partial correlation statistical package for social sciences, New York, 1970, McGrawHill Book Co. Rowland, M., Thomson, P. D., Guichard, A., and Melmon, K. L.: Disposition kinetics of lidocaine in normal subjects, Ann. N. Y. Acad. Sci. 179:383-398, 1971. Smith, E. R., and Duce, B. R.: The acute antiarrhythmic and toxic effects in mice and
676
Halkin et al.
dogs of 2-ethylamino-2' ,6'-acetoxylidine (L86), a metabolite of lidocaine, J. Pharmacol. Exp. Ther. 179:580-585, 1971. 9. Strong, 1. M., and Atkinson, A. J., Jr.: Simultaneous measurement of plasma concentrations of lidocaine and its desethylated metabolite by mass fragmentography, Anal. Chem. 44:22872290, 1972. 10. Strong, J. M., Parker, M., and Atkinson, A. 1., Jr.: Identification of glycinexylidide in patients treated with intravenous lidocaine, CUN. PHARMACOL. THER. 14:67-72, 1973.
Clinical Pharmacology and Therapeutics
11. Thomson, P. D., Rowland, M., and Melmon, K. L.: The influence of heart failure, liver disease and renal failure on the disposition of lidocaine in man, Am. Heart J. 82:417-421, 1971. 12. Thomson, P. D., Melmon, K. L., Richardson, J. H., Cohn, K., Steinbrunn, W., Cudihee, R., and Rowland, M.: Lidocaine pharmacokinetics in advanced heart failure, liver disease and renal failure in humans, Ann. Intern. Med. 78:499-508, 1973.
Hillel Halkin, M.D., * Peter Meffin, Ph. D., Kenneth L. Melmon, M.D., and Malcolm Rowland, Ph.D. San Francisco, Calif. Division of Clinical Pharmacoiogy, the Departments of Medicine and Pharmacology, School of Medicine, the Department of Pharmacy, School of Pharmacy, and the Cardiovascular Research Institute, University of California, San Francisco
The disposition kinetics and metabolism of lidocaine have been the subject of many recent investigations. 3 , 5, 7 Monoethylglycinexylidide (MEGX), the metabolite that arises from the N-deethylation of lidocaine, has been shown to share some of the pharmacologic properties of Supported in part by the Bay Area Heart Association and by National Institutes of Health Grants Nos. GM 16496, GM 0000 I. and GM 01791. Received for publication Nov. 2, 1974. Accepted for publication March 17. 1975. Reprint requests to: M. Rowland. Ph.D., Department of Pharmacy, University of California, San Francisco, San Francisco, Calif. 94143. • Merck International Fellow in Clinical Pharmacology; current address: Department of Medicine, Sheba Medical Center. Tel Hashomer. Israel.
the parent compound. 2 , 8 Previous studies have suggested that, in some patients, accumulation of MEGX during the course of the administration of lidocaine may contribute to the occurrence of the signs and symptoms of central nervous system toxicity that previously were attributed to the drug itself.9, 10 The concentrations of lidocaine and MEGX were measured in the blood of 31 patients who were receiving lidocaine infusions for the prevention or treatment of cardiac arrhythmias. Aspects of the pharmacokinetics of the metabolite were analyzed in a subgroup of the 31 patients; clinical correlates for the concentrations of MEGX in blood were sought for the entire group. 669
670
Clinical Pharmacology and Therapeutics
Halkin et al.
Materials and methods
We attempted to obtain reasonable estimates of the plateau levels of both lidocaine and MEGX by taking single samples of blood as late as possible after the attending physician had commenced lidocaine infusions. In most cases this was at least 10 hr after the initiation of lidocaine therapy. We did not interfere with or try to influence the manner in which lidocaine was given. A detailed history of lidocaine dosing (boluses and rates of infusion) was recorded for each patient by the nursing staff. Clinical data relating to history, physical findings, and laboratory results were obtained from the patients' charts, with particular emphasis on the presence or absence of signs and symptoms of congestive heart failure (peripheral edema, pulmonary congestion, elevated jugular venous pressure, gallop rhythm). In 3 of the 31 patients the lidocaine hydrochloride infusion rate was controlled with the use of a Harvard pump, at a rate of 2.5 mg/min; 20 samples of blood were obtained over the II-hr course of the infusion and after its discontinuation. Chemical analysis. The concentrations of lidocaine in blood were determined by the use of gas chromatography. 7 The concentrations of MEGX in blood were determined by a specific gas chromatographic method: A Varian series 1200 gas chromatograph fitted with a nickel-63 electron-capture detector was used for the analysis. Glass columns, 1.8 m, 0.3 cm o.d., packed with 3% OV-17 on Gas-Chrom-Q, 100120 mesh, were used. The carrier gas (5% methane in argon) had a flow rate of 20 ml/ min. The oven was maintained at 235 C, the injector port at 250 0 C, and the detector at 3200 C. The following were added to a 10 ml screwtopped tube: 0.05 to I ml of whole blood or plasma containing 10 to 100 ng of MEGX, together with internal standard solution (50 ng in 100 ILl of water), lOO J.LI of 2N NaOH and 3 ml of analytical reagent grade pentyl acetate. The internal standard was 3' -methoxy-2-ethylamino acetanilide hydrochloride (mp, 149 0 to 1500 C). The tube was then fitted with a Teflonlined screw- top and the contents were mixed vigorously for 2 min. After mixing, the tube was centrifuged and approximately 2.5 ml of 0
the pentyl acetate were transferred to a second 10-ml tube that had a tapered portion at the base of about 200 ILl capacity. To the second tube were added lOO ILl of 0.1 N H 2S04 , and the contents were then centrifuged. The pentyl acetate was removed and discarded. An additional 1 ml of pentyl acetate was added to the tube and was then mixed and centrifuged and the pentyl acetate discarded. Sodium hydroxide (20 ILl; 2 N) and 100 ILl of pentyl acetate were added to the H2 S04 solution that remained in the base of the tube. The tube contents were then mixed and centrifuged as described previously. Pentafluorobenzoyl chloride, * 20J.LI, of a freshly prepared 0.2% solution in benzene, was added to the pentyl acetate phase and the tube was allowed to sit at room temperature for 2 to 3 min. The contents of the tube were again mixed and centrifuged as described previously and 0.5 to I ILl of the pentyl acetate was injected into the gas chromatograph. The following modifications were made on samples containing amounts of MEGX greater than 100 ng, which enabled measurements of MEGX in the range of 100 to 1,000 ng. In the initial step of the extraction the amount of internal standard added was increased to 500 ng and the extraction was carried out as described previously. The final extraction was made with 200 J.LI of pentyl acetate and the derivatization was carried out with 20 ILl of 1.0% solution of pentafluorobenzoyl chloride in benzene. Only 0.1 to 0.5 J.LI of the pentyl acetate was injected into the chromatograph. Under the chromatographic conditions described previously, the peaks that resulted from MEGX and the internal standard had retention times of 3.3 and 4.7 min, respectively. Calibration curves were prepared by adding known amounts of MEGX to blood or plasma, which were then taken through the assay procedure. The plot of the peak height ratio of the derivative of MEGX to that of the internal standard vs the amount of MEGX added was linear over the two ranges examined (10 to 100 ng and 100 to 1,000 ng). Such a calibration curve is shown for the range 10 to 100 ng in • Pentafluorobenzoyl chloride was supplied by Pierce Chemical Co., Rockford, Ill.
Lidocaine and metabolite levels
Volume 17 Number 6
~~~
UDOCA~E
,....
:·"i·-e.!--·--·-.·-..:.·--=----.
~ 05~ ~
~
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•
7/~
0.2 (
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43 I{
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INFUSION
(Img/Kg)
(34/lg/mI!Kg)
y"
~
PAlIEN " ,
ID 12
~ HRS
· V I o t.
14
BOLUS (15mg/Kg)
A
~.--
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PATIENT 30
;
• •
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.
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.' \'.
MEGX
• __e
671
2
4
6
8
12
10
14
~ HRS
INFUSION (33)Jg/Kg/min)
Fig. 1. Observed (e) blood concentrations and fitted curves (-) of lidocaine and MEGX in 2 patients receiving a bolus and constant infusion of lidocaine.
Table I. Calibration curve for MEGX from blood
MEGX added to blood (ng)
Peak height ratio MEGX: Internal standard
Peak height ratio MEGX: Internal standard
ng MEGX
0.380 0.676 1.07 2.77 3.50
10
20
30 80
100
0.038 0.034 0.036 0.035 0.035
The data were fitted to the regression equation. y = 0.0347x
+ 0.0129. r
= 0.99985.
Table I. Calibration curves prepared from water, plasma, or whole blood did not differ significantly. No interfering peaks were observed when plasma or blood obtained from patients who had not received lidocaine was taken through the assay procedure. The precision of the method was determined by replicate assays of 5 samples that contained 30 ng of MEGX. The per cent relative standard deviation of the mean was 0.882%. No contribution of lidocaine to the MEGX assay, nor of MEGX to the lidocaine assay, was observed when control plasma samples were spiked with known quantities of these compounds. Results
The blood concentration-time curves for lidocaine and MEGX in 2 of the patients re-
ceiving infusions at a rate of 2.5 mg/min are shown in Fig. I. The lidocaine and MEGX data were fitted to the model depicted in Fig. 2 with the use of the program NONLIN. * Each datum was weighted by the reciprocal of the square of its value. Estimates of the various pharmacokinetic parameters and the steadystate blood concentrations of lidocaine and MEGX are listed in Table 11. Clinical data, average dosing rates (calculated by dividing the total amount administered by the infusion period), and individual patient blood concentrations of lidocaine and MEGX for all patients are listed in Table Ill. Also listed are the concentrations, which are normalized to a 10 mcg/ ruin/kg infusion rate. * Metzler. zoo. Mich.
c.:
Statistics Department. the Upjohn Co .. Kalama-
Halkin et al.
672
Clinical Pharmacology and Therapeutics
Table II. Derived pharmacokinetic parameters for lidocaine and MEGX Lidocaine
Subject
Infusion rate (mglmin)
28 29 30
2.5 2.5 2.5
Distribution
(min)
TV2
Volume of distribution (l/kg)
Steadystate concentration (mcglml)
Clearance (ml/minlkg)
87 (23) 165 (75) 163 (50)
1.04 2.5 0.92
2.5 1.9 4.1
13.6 18.0 8.0
Elimination
TV2 (min)
10.2 (34)* 21.8 (27) 10.6 (34)
* Coefficient of variation. t
2
= I _
r
sum of sguared deviations corrected sum of squared deviations'
Table Ill. Clinical information and blood concentrations of lidocaine and MEGX
Patient
Age
Sex
1 2 3 4 5* 6 7 8 9 10
65 61 43 54 54 50 52
M M F F F F F F M M M M M M M M M M M M M M M M M M M M M M M
11
12 13 14 15 16 17
18 19 20 21* 22 23 24 25 26 27
28 29 30 31
64
65 51 55 55 55 55 55 51 55 58 56 76 68 77
45 36 55 69 53 43 52 70 68
* Patient experienced
Heart failure
0 0 0
+ + + + 0 0 0 0
+ 0 0 0 0 0
+ 0
+ + 0 0 0 0 0 0 0 0 0 0
Duration of lidocaine infusion (hr)
Rate of lidocaine infusion (mcglminlkg)
Blood concentration of lidocaine (mcglml)
Blood concentration of MEGX (mcglml)
12 8 8.5 18.5 15 6.5 5 10 12.5 20 5 16 15 27 14 23.5 52
6.2 143.3 47 107 65 27.5 47.1 65.6 54 21.5 16.5 31 46.5 28 55 50 67 47 49 35 18.5 24 28 24 23 38 30 34 35 33 33
1.7 7.6 2.4 7.4 9.8 2.3 8.1 3.1 1.8 0.4 1.7 4.9 2.5 3.9 2.3 3.3 21.7 3.2 3.2 1.8 3.5 2.2 6.2 2.7 3.4 10.6 7 2.5 1.9 4.1 6.3
0.2 0.5 0.45 0.7 0.6 0.4 0.7 0.5 0.2 0.35 0.2 1.4 0.5 0.4 0.6 0.1 0.5 2.5 0.3 0.9 4.2 0.3 0.8 0.3 0.35 1.4
72
48 27 48 37 11 11
11 11.5 11 11 11 11 11
central nervous system toxicity during lidocaine infusion.
1.2
0.5 0.6 0.9 0.75
Volume 17 Number 6
Lidocaine and metabolite levels
MEGX
(min)
Steadystate concentration (mcglml)
r2t
199 (29) 71 (13) 87 (56)
0.5 0.6 1.9
0.978 0.992 0.975
Distribution Ph (min)
Elimination
6.1 (24) 4 (60) 48 (63)
TV2
673
Separation of the patients on the basis of the presence or absence of congestive heart failure at the time of the lidocaine infusion allowed a comparison of the blood concentrations of lidocaine and MEGX in the two groups, as seen in Table IV. Partial correlation analysis 6 (Table V) revealed a significant positive correlation between the presence of congestive heart failure and MEGX levels in this group of patients. Lidocaine infusion rates and blood concentrations tended to be higher in the heart failure group, although this did not attain statistical significance. Discussion
Blood concentration of lidocaine 110 mcg Imin Ikg infusion rate
Blood concentration of MEGX/JO mcglminlkg infusion rate
2.7 0.53 0.5 0.7
0.32 0.035 0.096 0.065 0.092 0.15 0.15 0.076 0.037 0.16 0.12 0.47 0.11 0.14
1.5
0.84 1.7 0.47 0.33 0.19 1.0 1.5 0.54 1.4 0.42 0.66 3.2 0.68 0.65 0.52 1.9 0.92 2.2 1.1
1.5 2.8 2.3 0.74 0.54 0.12 0.19
Mean 1.1
0.11
0.020 0.075 0.53 0.061 0.26 2.27 0.13 0.29 0.13 0.15 0.37 0.40 0.15 0.17 0.27 0.23 0.245
The pharmacokinetic parameters for lidocaine derived for the 3 patients studied intensively are not significantly different from those found in normal volunteers. 7 In these 3 subjects, estimates of the distribution half-life and elimination half-life of MEGX were found to range between 4 and 48 min and 71 and 199 min, respectively (Table Ill). These data are insufficient for defining population estimates, but the elimination half-life of MEGX estimated by others! falls within the range we found. The lack of clearance value for MEGX (which can be defined only by independent administration of the metabolite), and the uncertainty of knowing whether a fraction of the formed MEGX is further metabolized in the liver and is not seen systemically, prevents an estimate of the fraction of the dose of lidocaine actually being metabolized via MEGX. Although the model chosen failed to fit the early MEGX levels, it was felt adequate to describe the overall disposition kinetics of lidocaine and MEGX. On average, the concentration achieved per 10 mcg/min/kg infusion rate is 1.1 mcg/ml (Table Ill), which agrees with that noted previously.4. 7 The variability is probably caused by the relative inconstancy of the infusion rate, the failure of all patients to be at steady state, and the diverse clinical status of the patients. MEGX levels generally were only one fourth of those of lidocaine. Other investigators suggest9 • !O that in some
674
Clinical Pharmacology and Therapeutics
Halkin et al.
Table IV. Influence of heart failure on MEGX and lidocaine blood concentrations
Heart failure *
Age (yr)
Rate of lidocaine infusion (mcglminlkg)
Duration of lidocaine infusion (hr)
Present (n = 8)
58,4 ± 3.2t
47.3 ± 9.9
26 ± 8
Absent (n = 23)
58.5 ± 2
41.4 ± 5.6
17.5 ± 2.6
Blood concentration of lidocaine (mcglml)
Blood concentration of MEGX (mcglml)
5.1 ± 1
1,4 ± 0,46 (p = 0.003)
4,4 ± 0.9
0.5 ± 0.1 (p = 0.003)
* As judged by the presence of two or more of the following: edema. pulmonary vascular congestion, elevated jugular venous pressure. gallop rhythm, tMean ± SEM.
Table V. Multivariate partial correlation analysis of MEGX and lidocaine blood concentrations Heart failure *
Infusion ratet
Infusion durationt
Lidocaine Concentration
NS
r = 0.33 p = 0.04
NS
MEGX Concentration
r = 0.5 p = 0.004
NS
r = 0.3 P = 0.062
* Controlling for
age, sex, duration, and rate of infusion.
t Controlling for age. sex. heart failure presence. and duration of infusion. tControlling for age, sex, he an failure presence, and infusion rate.
Lidocaine
Bolus + Infusion
•
n
I
}
Lidocaine
Disposition
I
MEGX
Disposition
Fig. 2. Model used to describe the pharmacokinetics of lidocaine and MEGX.
patients recelVlng lidocaine appreciable amounts of active metabolite may accumulate and contribute to the pharmacologic effects, both beneficial and toxic, that are seen clinically. Our results confirm and extend this suggestion. Three of the patients listed in Table III (Patients 19, 2l, 22) had MEGX blood con-
centrations similar to those of lidocaine, Studies in experimental animals have demonstrated the near equipotence of lidocaine and MEGX in producing convulsions. 2 , 8 Two patients in this series manifested signs of lidocaine toxicity (paresthesia and marked confusion) during the course of the lidocaine infusions. In one (Patient 5), these signs and symptoms of toxicity occurred 7 hr after the start of the infusion and lasted 2 hr after the infusion rate was diminished. In the other (Patient 21), the symptoms occurred 8 hr after the start of the infusion and lasted 1.5 hr after the infusion rate was dropped. The lack of neurologic sequelae and of any other clinical occurrence or pharmacologic intervention at the time of the appearance of this symptom-complex suggests its relation to lidocaine infusion. The amelioration of the clinical signs after the decrease in the infusion rate supports this contention. In Patient 5, the toxicity could be explained by the lidocaine blood concentration alone (9.8 mcg/ml), but in Patient 21 the MEGX concentration
Lidocaine and metabolite levels
Volume 17 Number 6
probably contributed to the reaction (lidocaine 3.5 mcg/ml, MEGX 4.2 mcg/ml), although the contribution of other metabolites of lidocaine cannot be discounted. Of the 31 patients studied, 22 had lidocaine levels below 5 mcg/ml, and 27 had levels below 8 mcg/ml. Four had higher levels, one of whom (Patient 5) manifested toxicity. Toxicity is usually anticipated above 8 mcg/mI4; however given the high variability frequently seen in the responsiveness of individuals to drugs, we hesitate to draw any conclusions from our data regarding the relative safety of higher concentrations of lidocaine. Table IV shows an analysis of the blood level data for lidocaine and MEGX in the 31 patients and is based on the presence or absence of congestive heart failure. No difference was found between the two groups with respect to age, duration of the infusion of lidocaine, or lidocaine concentrations, although MEGX levels were significantly higher in the heart failure group. Multivariate partial correlation analysis (Table V) revealed a significant positive correlation between lidocaine concentrations and the lidocaine infusion rates, but no correlation between lidocaine levels and the presence of heart failure. The absence of this correlation is not in conflict with previous reportsll' 12; it was probably obscured in our patients by the variable dosages and by the varying degrees of congestive heart failure that were assessed at the bedside and the relative inconstancy in the rates of lidocaine infusion. Nevertheless, MEGX blood concentrations were significantly higher when heart failure was present. This correlation maintained its significance even after the patient's age, sex, and the duration and rate of the lidocaine infusion had been taken into account. Conditions of hemodynamic instability, and congestive heart failure in particular, have been shown to reduce the volume of distribution and plasma clearance of lidocaine. 1!' 12 Our data indicate that a similar influence may be exerted by these conditions upon elimination of MEGX, which is normally further metabolized in the liver. 10 Thus congestive heart failure, in addition to causing inappropriately high lidocaine levels for any given rate of lidocaine
675
infusion, may further complicate the therapeutic setting by causing excessive accumulation of the active metabolite. It may be that the elimination of MEGX is also influenced by hepatic blood flow. The reason that a higher MEGX/lidocaine ratio is not seen in all patients with heart failure may be due to changes in the fraction of lidocaine that is metabolized via MEGX. This possibility can be explored only by direct administration of the metabolite. A final practical consideration is that the halflife of MEGX is similar to that of lidocaine. Interruption of the lidocaine infusion should therefore usually result in a relatively rapid decline in the blood levels of both compounds, and prolonged presence of this metabolite in the circulation probably occurs only in those instances in which the elimination of lidocaine is markedly slowed. The authors are grateful to Astra Pharmaceutical Products, Inc., Worcester, Mass., for kindly providing a sample of MEGX.
References I. Adjepon-Yamoah, K. K., and Prescott, L. F.:
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Lignocaine metabolism in man, Br. l. Pharmacol. 47:672-673, 1973. Blumer, l., Strong, l. M., and Atkinson, A. l., lr.: The convulsant potency of lidocaine and its N-dealkylated metabolites, In press, l. Pharmacol. Exp. Ther. 186:31-36, 1973. Boyes, R. N., Scott, D. B., lebson, P. l., Goodman, M. 1., and lulian, D. G.: Pharmacokinetics of lidocaine in man, CUN. PHARMACOL. THER. 12: 105-116, 1971. Gianelly, R., Von der Groeben, l. 0., Spivack, A. P., and Harrison, D. c.: Effect of lidocaine on ventricular arrhythmia in patients with coronary heart disease, N. Engl. l. Med. 277: 1215-1219, 1967. Keenaghan, l. B., and Boyes, R. N.: The tissue distribution, metabolism and excretion of lidocaine in rats, guinea pigs, dogs and man, l. Pharmacol. Exp. Ther. 180:454-463, 1972. Nie, N. H., Bent, D. H., and Hull, C. H., editors: Partial correlation statistical package for social sciences, New York, 1970, McGrawHill Book Co. Rowland, M., Thomson, P. D., Guichard, A., and Melmon, K. L.: Disposition kinetics of lidocaine in normal subjects, Ann. N. Y. Acad. Sci. 179:383-398, 1971. Smith, E. R., and Duce, B. R.: The acute antiarrhythmic and toxic effects in mice and
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dogs of 2-ethylamino-2' ,6'-acetoxylidine (L86), a metabolite of lidocaine, J. Pharmacol. Exp. Ther. 179:580-585, 1971. 9. Strong, 1. M., and Atkinson, A. J., Jr.: Simultaneous measurement of plasma concentrations of lidocaine and its desethylated metabolite by mass fragmentography, Anal. Chem. 44:22872290, 1972. 10. Strong, J. M., Parker, M., and Atkinson, A. 1., Jr.: Identification of glycinexylidide in patients treated with intravenous lidocaine, CUN. PHARMACOL. THER. 14:67-72, 1973.
Clinical Pharmacology and Therapeutics
11. Thomson, P. D., Rowland, M., and Melmon, K. L.: The influence of heart failure, liver disease and renal failure on the disposition of lidocaine in man, Am. Heart J. 82:417-421, 1971. 12. Thomson, P. D., Melmon, K. L., Richardson, J. H., Cohn, K., Steinbrunn, W., Cudihee, R., and Rowland, M.: Lidocaine pharmacokinetics in advanced heart failure, liver disease and renal failure in humans, Ann. Intern. Med. 78:499-508, 1973.
