Kinetic isotope effect in the metabolic demethylation of temazepam

Abstract

The kinetics of the metabolic demethylation of temazepam were examined. Oxidative cleavage of the 1-methyl C–H bonds is rate-determining in the 13 000 g supernatant of mouse liver homogenate, as shown by the primary deuterium isotope effect (3.6) for demethylation of 1-CD₃-labelled temazepam. With a reduced supply of NADPH, reduction of the cytochrome P-450–substrate complex becomes rate-limiting. Decomposition of the 1-N-hydroxymethyl intermediate is fast enough not to influence the rate of demethylation.