Influence of enzyme induction and inhibition on the oxidation of nifedipine, sparteine, mephenytoin and antipyrine in humans as assessed by a "cocktail" study design

Nifedipine (NF), sparteine (SP), mephenytoin (MP) and antipyrine (AP) were administered simultaneously ("cocktail" design) to 15 healthy subjects, including 4 poor metabolizers (PM) of SP and 4 PMs of MP, on three different occasions: without pretreatment, after pentobarbital (PB) pretreatment and together with cimetidine (cim). Concentrations of AP, NF, its pyridine metabolite 2,6-dimethyl-4-(2-nitrophenyl)-pyridine-3,5-dicarboxylate-methylester (M-O), SP, dehydrosparteine (DHS) were determined in plasma; 2,6-dimethyl-4-(2-nitrophenyl)-pyridine-3,5-dicarboxylate-monomethyle ster (which is ester hydrolyzed M-O), SP, DHS, 4-hydroxymephenytoin, AP and metabolites 3-hydroxymethylantipyrine, norantipyrine and 4-hydroxyantipyrine were measured in urine. Clearance of NF had increased 270% after PB and decreased 32% with cim. Area under the plasma-concentration time curve of M-O and urinary excretion of 2,6-dimethyl-4-(2-nitrophenyl)-pyridine-3,5-dicarboxylate-monoethyles ter had also decreased after PB. Neither extensive metabolizers nor PMs of SP and MP were sensitive to PB treatment, but sparteine clearance was reduced 55% by cim in extensive metabolizers and 59% in PMs. Ratio SP/DHS in urine was hardly influenced by cim. AP oxidation was significantly induced and inhibited by PB and cim, respectively. The cocktail study design seems to be suitable to assess induction and inhibition of the metabolism of the applied model substrates, which are metabolized by at least partly independent isozymes of the cytochrome P-450 system, simultaneously.