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.>metabolites of AP were highest for CL->HMA and CL->NORA (>0.80) and lowest for CL_>OHA (0.63). High correlation coefficients also were found between CLTH and CL_>OHA (0.89) and CL_>HMA (0.80). 4 Ideal relationships, defined by a slope of the orthogonal regression line equal to unity, did exist between CLHB and CL_>HMA as well as CL_>NORA and between CLTH and CLAP as well as CL_>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 intraindividual variation in drug oxidation.

No abstract

No abstract

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.