Antipyrine (AP), hexobarbital (HB) and theophylline (TH) were administered simultaneously ('cocktail' design) to 24 patients with various types of liver disease. Clearance (Cl) of AP, HB and TH and formation clearance of the AP-metabolites 3-hydroxymethylantipyrine (HMA), norantipyrine (NORA) and 4-hydroxyantipyrine (OHA) were determined and correlation coefficients and orthogonal least-squares regression lines calculated between the clearance and formation clearance parameters. The results were compared with those obtained in a study in which the same 'cocktail' was administered to 26 healthy control subjects. In the patients ClAP, ClHB and ClTH were 23.0 +/- 14.3 ml min-1, 206 +/- 128 ml min-1 and 39.9 +/- 26.1 ml min-1 respectively. All values were considerably lower than those found in the control subjects. With regard to AP metabolism preferential impairment of NORA formation was observed. Relatively high correlation coefficients were found between ClAP, ClHB and ClTH, which suggests, like the results of orthogonal regression analysis, a strong correlation between total metabolism of these probe drugs. Therefore it is likely that impairment in oxidation in patients with liver disease not only leads to reduction in clearance but also to reduced substrate selectivity of cytochrome P-450 isozymes.

1,3-Dibromopropane (1,3-DBP) was administered i.p. in doses ranging from 5.6 to 54 mg to male Wistar rats. Four different mercapturic acids, viz. N-acetyl-S-3-bromopropyl-(MA I), N-acetyl-S-3-chloropropyl-(MA II), N-acetyl-S-2-carboxyethyl-(MA III) and N-acetyl-S-3-hydroxypropyl(-1-)cysteine (MA IV) were synthesized and identified as metabolites in urine by g.l.c.-mass spectrometry. 1,1,3,3-Tetradeutero-1,3-dibromopropane was used to study the mechanism of formation of the mercapturic acids in more detail. It was found that in the formation of MA IV a reactive episulphonium ion could be involved. Gas chromatographic quantification of the mercapturic acids (mercapturic acid assay) was correlated with a spectrophotometric thioether determination of the metabolites (thioether test). At doses up to 30 mg of 1,3-DBP, excretion of mercapturic acids was virtually complete in 24 h urine and amounted to about 19% of the dose (11.3% MA I, 4.9% MA II, 2.6% MA III and 0.2% MA IV). From excretion rate curves a half-time t1/2 was calculated as being about 4.5 h. A plateau in the dose-excretion curve was observed at 1,3-DBP doses higher than 40 mg, probably caused by glutathione depletion.

Nifedipine, sparteine and phenytoin were administered orally to eight healthy subjects separately and as a 'cocktail' on four different occasions to investigate any kinetic interactions. All subjects were extensive metabolizers of sparteine. After drug intake plasma and urine samples were collected up to 32 h and the concentrations of parent drugs and main metabolites were measured. Clearances and formation clearances were not significantly different after single substrate and 'cocktail' administration. Low or non significant correlation coefficients were found between the oxidation of the individual substrates or formation of their metabolites. With this strategy of simultaneous administration of substrates ('cocktail') it appears possible to characterize (and correlate) activities of different cytochrome P-450 isoenzymes, without the disturbing influence of intraindividual variation of drug oxidation with time.

1 In a phenotyped panel of healthy subjects correlations were studied between the oxidation of mephenytoin, phenytoin, methylphenytoin and phenobarbitone, with respect to the formation of their 4-hydroxy metabolites (OH-). 2 On different occasions phenotyped extensive metabolizers (EM; n = 16) and poor metabolizers (PM; n = 4) of mephenytoin received phenytoin (100 mg), methylphenytoin (100 mg) and phenobarbitone (50 mg) and urine was collected up to 24 h. The excreted 4-hydroxy metabolites of all compounds were measured by h.p.l.c. 3 Urinary recovery of OH-phenytoin was 31.0 ± 11.7%, of OH-methylphenytoin 3.4 + 2.7% and of OH-phenobarbitone 1.4 ± 1.2%. No correlation was found between the recovery of OH-mephenytoin and OH-phenytoin. A subject who produced virtually no OH-phenytoin was an EM of mephenytoin, confirming a dissociation of mephenytoin polymorphism and phenytoin hydroxylation. 4 The correlation coefficient for OH-mephenytoin and OH-methylphenytoin recovery was 0.71 (Spearman rank, P = 0.002). The PMs of mephenytoin excreted the least amount of OH-methylphenytoin, suggesting a cosegregation of the 4-hydroxylation pathways. No correlation was found between the urinary recovery of OH-phenobarbitone and that of the other 4-hydroxy metabolites.Keywords mephenytoin polymorphism phenytoin methylphenytoin and phenobarbitone hydroxylation cytochrome P-450

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