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. Empen thrin did not delay the clearance of pentobarbital from serum in dogs. In addition, empenthrin dose-dependently inhibited in vitro metabolis m of pentobarbital in mice, but not in rats, guinea pigs, hamsters or rabbits. Lineweaver-Burk plots indicated that the inhibition was compe titive in mice. Microsomal fractions of recombinant yeast expressing h uman cytochrome P-450 (CYP)s were used to determine the inhibitory eff ect of empenthrin on pentobarbital metabolism in humans. CYP2B6 and CY P2D6 were responsible for biotransformation of pentobarbital to a pent obarbital 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 inhibi t the pentobarbital metabolism catalyzed by these two CYPs. These find ings suggest that the inhibition of pentobarbital metabolism by empent hrin in mice does not occur in other species including humans.