Correlation between the in vivo metabolism of hexobarbital and antipyrine in rats with a portacaval shunt

To investigate how hepatic malfunction affects the disposition of hexobarbital (HB), an intermediate 'high-clearance' compound, and antipyrine (AP), a low-clearance compound, as well as the correlation between the rates of elimination of these drugs, their pharmacokinetics, were studied in control rats (n = 8) and in rats with a portacaval shunt (PCS; n = 9). Blood concentrations of parent drugs were measured, and urinary excretion of the following metabolites was determined: 3-hydroxymethylantipyrine (HMA), 4-hydroxyantipyrine and norantipyrine as primary metabolites of AP, and 3'-hydroxyhexobarbital (OH-HB) and 3'-ketohexobarbital (K-HB) as primary metabolites of HB. Blood elimination half-lives of AP and HB were more than four times longer in PCS rats than in control rats, increasing from 63.7 +/- 3.9 to 291 +/- 66 min, and from 20.1 +/- 1.8 to 84.2 +/- 7.6 min, respectively. Intrinsic clearance of HB (CLint, HB) was 167 +/- 19 ml/min/kg in controls and 27 +/- 4 ml/min/kg in PCS rats (CLpcs, HB). Intrinsic clearance of AP (CLint, AP) in control rats was 15.1 +/- 0.7 ml/min/kg and 5.9 +/- 0.7 ml/min/kg in PCS rats (CLpcs, AP). PCS reduced clearance for production of metabolites (CLMn) of AP by 50%, but CLMn of HB metabolites was decreased by more than 80%. The CLint, AP, CLint, HB CLpcs, HB, CLpcs, AP, and CLMn data were correlated. Total clearance correlated better in PCS rats than in control rats: r = 0.77 versus r = 0.10, respectively, thus suggesting a decrease in substrate selectivity under pathological conditions. CLOH-HB+K-HB, reflecting the major metabolic pathway of HB, correlated most closely with CLHMA in PCS (r = 0.91). Therefore, the underlying metabolic conversions of HB and AP may be mediated by the same or very similar forms of cytochrome P-450. Our results suggest that the predictive value of the model substrate approach is valid under pathological conditions.