Metabolism of megestrol acetate and related progesterone analogues by liver preparations in vitro

Abstract

The rates of metabolism of megestrol acetate, 17[alpha]-acetoxy-6[alpha]-methyl-progesterone, 6[alpha]-methyl-progesterone, 17[alpha]-acetoxyprogesterone and progesterone by liver microsome[long dash]supernatant fractions from female rats and rabbits have been compared. Introduction of the 6[alpha]-methyl group into the progesterone molecule markedly decreased the metabolism by liver microsome[long dash]supernatant preparations in the rat but not in the rabbit. When 17[alpha]-acetoxy was the substituting group, metabolism was diminished in the rabbit but not in the rat preparations. Introduction of both the 6[alpha]-methyl and 17[alpha]-acetoxy groups into the progesterone molecule markedly decreased the rate of metabolism by liver microsome-supernatant preparations of both species. The [DELTA]6-bond in megestrol acetate confers additional resistance to metabolism by rabbit-liver preparations. It is proposed that the observed inhibition of metabolism by these substituents in the progesterone molecule partly or wholly explains the enhanced activity of megestrol acetate.