Inhibition of hepatic oxidative xenobiotic metabolism by piperonyl butoxide

Abstract

The oxidative metabolism of piperonyl butoxide to a metabolite which forms a complex with reduced cytochrome P-450 is not inhibited by cyanide, but is prevented by the mercurial mersalyl. The apparent K m for this oxidation of piperonyl butoxide is low, being 65 μM. The inhibition of ethylmorphine N-demethylation by piperonyl butoxide in vitro is proportional to the amount of cytochrome P-450 present as the cytochrome P-450-piperonyl butoxide metabolite complex. Piperonyl butoxide shows mixed inhibition kinetics when present during ethylmorphine N-demethylation, i.e. competitive during the formation of the piperonyl butoxide metabolite, and noncompetitive once the metabolite is complexed with cytochrome P-450. Differences in the rate of formation of the piperonyl butoxide metabolite-cytochrome P-450 complex in liver microsomes from rats and mice can account for the greater sensitivity of mice to piperonyl butoxide inhibition of drug metabolism. Enhancement of absorption spectra in turbid solutions, such as piperonyl butoxide dispersions, is examined and discussed.