Species difference in the inhibition of pentobarbital metabolism by empenthrin.

Empenthrin, synthetic pyrethroid, prolonged the pentobarbital-induced sleeping time in mice, but not in rats, guinea pigs or hamsters. Empenthrin did not delay the clearance of pentobarbital from serum in dogs. In addition, empenthrin dose-dependently inhibited in vitro metabolism of pentobarbital in mice, but not in rats, guinea pigs, hamsters or rabbits. Lineweaver-Burk plots indicated that the inhibition was competitive in mice. Microsomal fractions of recombinant yeast expressing human cytochrome P-450 (CYP)s were used to determine the inhibitory effect of empenthrin on pentobarbital metabolism in humans. CYP2B6 and CYP2D6 were responsible for biotransformation of pentobarbital to a pentobarbital alcohol identified as 5-ethyl-5-(1'-methyl-3'-hydroxybutyl) barbituric acid. The structure of pentobarbital fit the criteria for a CYP2D6 substrate on computational analysis. Empenthrin did not inhibit the pentobarbital metabolism catalyzed by these two CYPs. These findings suggest that the inhibition of pentobarbital metabolism by empenthrin in mice does not occur in other species including humans.