European Journal of Clinical Pharmacology © by Springer-Verlag 1979
Europ. J. clin. Pharmacol. 15, 57-61 (1979)
The Metabolism of Methaqualone in Patients with Biliary Cirrhosis or Secondary Carcinoma of the Liver D. Burnett l, C. N. Reynolds 2, and K. Wilson 2 1BiochemistryDepartment, St. Albans, City Hospital, St. Albans, Herts, U. K. 2BiologicalSciences, The Hatfield Polytechnic,Hatfield, Herts, U. K.
Summary. The metabolism of methaqualone has been studied in three patients with secondary carcinoma of the liver and two with biliary cirrhosis. The urinary excretion of five C-monohydroxy metabolites and the N-oxide was studies in the 24 h period immediately after oral dosing with 250 mg methaqualone (Melsed). In both patients with biliary cirrhosis and one with primary carcinoma of the bile duct or pancreas with secondaries in the liver the pattern of metabolites was normal. In a patient with oat cell carcinoma with secondaries in the liver some metabolite patterns were disturbed and increased metabolite excretion occurred. A patient with primary carcinoma of the breast with secondaries in the liver gave a completely abnormal metabolite pattern. Key words: Metaqualone, biliary cirrhosis, liver carcinoma; drug metabolism.
Both acute and chronic liver disease may significantly alter the disposition of drugs particularly those that are normally cleared by hepatic metabolism. The majority of previous studies which have attempted to evaluate hepatic metabolic activity in liver disease patients have measured the plasma half-lives of drugs such as antipyrine and paracetamol. These studies are complicated by concomitant changes in protein binding, hepatic blood flow, volumes of distribution and perhaps renal function. In addition, such patients are generally receiving other drug therapy which it is not possible to discontinue during the course of the study. Ethical considerations also make it difficult to justify taking blood samples in these patients. Whilst a number of recent studies have attempted to evaluate the effects of alcoholic cirrhosis and hepatitis and hepatic metabolic activity, less information is avail-
able concerning the effects of biliary disorders and neoplastic conditions on this activity. In an attempt to assess the effects of secondary carcinoma of the liver and of primary or secondary biliary cirrhosis on hepatic metabolic function we have avoided some of the complex pharmacokinetic interrelationships inherent in plasma half-life determinations by investigating urinary metabolite excretion and the pattern of metabolites produced by competitive pathways. Three of the patients involved in the study were receiving other drug therapy and no blood data was obtained from any of the patients, but in order to gain a preliminary insight into the effects of these conditions on hepatic metabolism, the approach taken was considered to be justifiable. The orally active hypnotic methaqualone (2methyl-3-o-tolyl-4(3H)-quinazolinone) was used in the study. When given in oral therapeutic doses to healthy adults it undergoes C-oxidation to five monohydroxy derivatives which are excreted as their highly polar glucuronides (Burnett et al., 1976) and N-oxidation to the N-oxide (Reynolds et al., 1976). Less than 1% of the dose is renally excreted unchanged (Reynolds et al., 1976) and less than 4% is excreted via the bile (Smyth et al., 1973). Interindividual variation in the pattern of the six metabolites has been shown tO be small and no differences to exist between males and females (Wilson et al., 1978).
Materials and Methods Determination of Methaqualone and Methaqualone Metabofite Excretion in Urine Methaqualone and methaqualone-N-oxide were determined by the method of Reynolds et al. (1976) and the five C-monohydroxy metabolites (2'- and 20031-6970/79/0015/0057/$01.00
58
D. Burnett et al.: Methaqualone in Patients with Biliary Cirrhosis or Carcinoma of the Liver
Table 1. Clinical and biochemical details of patients studied Patient Age Sex Diagnosis and other drug therapy
RM
26
M
CA
47
M
JD
49
F
ES
71
F
AC
55
F
ACTH secreting oat-cell carcinoma of the lung with secondaries in the liver* Cyclophosphamide; perphenazine (5 mg 4 hourly); diamorphine (as required); spironolactone (50 mg daily) Primary carcinoma of bile duct or pancreas with secondaries in the liver* No other drug therapy Primary biliary cirrhosis* No other drug therapy Secondary biliary cirrhosis* Frusemide (80 mg daily); spironolactone (200 mg daily) Primary carcinoma of the breast with secondary in the liver Paracetamol (when required); thyroxine (0.2 mg daily) Normal biochemical values
Total Total Albumin Globulin Bilirubin g/1 g/1 ~M
SGPT U/1
SGOT U/1
y-GT U/1
AP U/1
LDH U/I
34
28
103
18
53
496
547
782
38
34
7
16
18
307
574
505
44
55
63
27
36
1110
957
257
33
33
63
4
11
67
270
148
36
43
8
25
66
361
919 2270
35-50
20-35
Europ. J. clin. Pharmacol. 15, 57-61 (1979)
The Metabolism of Methaqualone in Patients with Biliary Cirrhosis or Secondary Carcinoma of the Liver D. Burnett l, C. N. Reynolds 2, and K. Wilson 2 1BiochemistryDepartment, St. Albans, City Hospital, St. Albans, Herts, U. K. 2BiologicalSciences, The Hatfield Polytechnic,Hatfield, Herts, U. K.
Summary. The metabolism of methaqualone has been studied in three patients with secondary carcinoma of the liver and two with biliary cirrhosis. The urinary excretion of five C-monohydroxy metabolites and the N-oxide was studies in the 24 h period immediately after oral dosing with 250 mg methaqualone (Melsed). In both patients with biliary cirrhosis and one with primary carcinoma of the bile duct or pancreas with secondaries in the liver the pattern of metabolites was normal. In a patient with oat cell carcinoma with secondaries in the liver some metabolite patterns were disturbed and increased metabolite excretion occurred. A patient with primary carcinoma of the breast with secondaries in the liver gave a completely abnormal metabolite pattern. Key words: Metaqualone, biliary cirrhosis, liver carcinoma; drug metabolism.
Both acute and chronic liver disease may significantly alter the disposition of drugs particularly those that are normally cleared by hepatic metabolism. The majority of previous studies which have attempted to evaluate hepatic metabolic activity in liver disease patients have measured the plasma half-lives of drugs such as antipyrine and paracetamol. These studies are complicated by concomitant changes in protein binding, hepatic blood flow, volumes of distribution and perhaps renal function. In addition, such patients are generally receiving other drug therapy which it is not possible to discontinue during the course of the study. Ethical considerations also make it difficult to justify taking blood samples in these patients. Whilst a number of recent studies have attempted to evaluate the effects of alcoholic cirrhosis and hepatitis and hepatic metabolic activity, less information is avail-
able concerning the effects of biliary disorders and neoplastic conditions on this activity. In an attempt to assess the effects of secondary carcinoma of the liver and of primary or secondary biliary cirrhosis on hepatic metabolic function we have avoided some of the complex pharmacokinetic interrelationships inherent in plasma half-life determinations by investigating urinary metabolite excretion and the pattern of metabolites produced by competitive pathways. Three of the patients involved in the study were receiving other drug therapy and no blood data was obtained from any of the patients, but in order to gain a preliminary insight into the effects of these conditions on hepatic metabolism, the approach taken was considered to be justifiable. The orally active hypnotic methaqualone (2methyl-3-o-tolyl-4(3H)-quinazolinone) was used in the study. When given in oral therapeutic doses to healthy adults it undergoes C-oxidation to five monohydroxy derivatives which are excreted as their highly polar glucuronides (Burnett et al., 1976) and N-oxidation to the N-oxide (Reynolds et al., 1976). Less than 1% of the dose is renally excreted unchanged (Reynolds et al., 1976) and less than 4% is excreted via the bile (Smyth et al., 1973). Interindividual variation in the pattern of the six metabolites has been shown tO be small and no differences to exist between males and females (Wilson et al., 1978).
Materials and Methods Determination of Methaqualone and Methaqualone Metabofite Excretion in Urine Methaqualone and methaqualone-N-oxide were determined by the method of Reynolds et al. (1976) and the five C-monohydroxy metabolites (2'- and 20031-6970/79/0015/0057/$01.00
58
D. Burnett et al.: Methaqualone in Patients with Biliary Cirrhosis or Carcinoma of the Liver
Table 1. Clinical and biochemical details of patients studied Patient Age Sex Diagnosis and other drug therapy
RM
26
M
CA
47
M
JD
49
F
ES
71
F
AC
55
F
ACTH secreting oat-cell carcinoma of the lung with secondaries in the liver* Cyclophosphamide; perphenazine (5 mg 4 hourly); diamorphine (as required); spironolactone (50 mg daily) Primary carcinoma of bile duct or pancreas with secondaries in the liver* No other drug therapy Primary biliary cirrhosis* No other drug therapy Secondary biliary cirrhosis* Frusemide (80 mg daily); spironolactone (200 mg daily) Primary carcinoma of the breast with secondary in the liver Paracetamol (when required); thyroxine (0.2 mg daily) Normal biochemical values
Total Total Albumin Globulin Bilirubin g/1 g/1 ~M
SGPT U/1
SGOT U/1
y-GT U/1
AP U/1
LDH U/I
34
28
103
18
53
496
547
782
38
34
7
16
18
307
574
505
44
55
63
27
36
1110
957
257
33
33
63
4
11
67
270
148
36
43
8
25
66
361
919 2270
35-50
20-35
