Relationship between the metabolism of antipyrine, hexobarbitone and theophylline in man as assessed by a 'cocktail' approach.

1. Three model substrates for the characterization of drug oxidation activity, antipyrine (AP), hexobarbitone (HB) and theophylline (TH), were administered to 26 healthy volunteers on two different occasions: in the first experiment a combination of AP (250 mg) and HB (250 mg) was given and in the second experiment TH (150 mg) was added to the former combination. 2. Plasma concentrations of AP, HB and TH and urinary excretion of TH and the three main metabolites of AP (3-hydroxymethylantipyrine: HMA, norantipyrine: NORA and 4-hydroxyantipyrine: OHA) were determined and the intrinsic clearance (CLint) of the three substrates and the clearance to the formation of AP metabolites were calculated. 3. The correlation coefficients between CLHB and CL-greater than metabolites of AP were highest for CL-greater than HMA and CL-greater than NORA (greater than 0.80) and lowest for CL-greater than OHA (0.63). High correlation coefficients also were found between CLTH and CL-greater than OHA (0.89) and CL-greater than HMA (0.80). 4. Ideal relationships, defined by a slope of the orthogonal regression line equal to unity, did exist between CLHB and CL-greater than HMA as well as CL-greater than NORA and between CLTH and CLAP as well as CL-greater than OHA. 5. Based on the results of correlation and regression analysis it can be concluded that isozymes of the cytochrome P-450 system responsible for the oxidation of HB and formation of HMA and NORA are very closely related and also that isozymes responsible for the oxidation of TH and formation of OHA show a very close relation. 6. With this strategy of simultaneous administration of substrates ('cocktail' approach) it seems possible to characterize and correlate activities of different P-450 isozymes and to investigate their in vivo substrate selectivity without the disturbing influence of intra-individual variation in drug oxidation.