Correlation between the metabolism of hexobarbital and aminopyrine in vivo in rats

Abstract

1. Two model substrates for oxidative hepatic enzyme activity, namely hexobarbital and aminopyrine, were simultaneously orally administered to rats, and blood concentrations of the substrates measured by g.l.c.

2. The apparent intrinsic clearances of hexobarbital (Cl^*_int.HB) and of aminopyrine (Cl^*_int.AM) were correlated in untreated rats, and in rats pretreated with phenobarbital. 3-methylcholanthrene, polychlorinated biphenyls or carbon tetrachloride. Cl^*_int.HB and Cl^*_int.AM were both increased by phenobarbital and polychlorinated biphenyl pretreatment. Pretreatment with 3-methylcholanthrene had hardly any effect, and carbon tetrachloride caused a strong diminution of Cl^*_int.HB and Cl^*_int.AM.

3. When the dose of aminopyrine was decreased, both Cl^*_int.HB and Cl^*_int.AM increased. This indicated that the primary metabolite of aminopyrine. monomethylaminopyrine. inhibits cytochrome P-450.

4. The correlation coefficient for all clearance data was 0·92 (N = 36). It was concluded that both hexobarbital and aminopyrine are metabolized in vivo by the same or closely related cytochrome P-450 isozymes, and both may be used as model substrates in vivo for metabolic conversions primarily mediated by the major phenobarbital-inducible cytochrome P-450 subspecies.