IN VITRO INHIBITION OF DRUG METABOLISM BY METABOLITES OF PROGESTERONE

¹ Department of Pharmacology, University of Illinois Medical Center, Chicago, Illinois

Oxidative drug metabolism is depressed during pregnancy when tissue and serum levels of progesterone and its metabolites are elevated. Progesterone and 25 ⁴-pregnene and pregnane derivatives were tested for an inhibitory effect on demethylation. Seven were more potent than progesterone; for example, pregnanedione was active at 4 x 10^-10M. Pregnanolone and pregnanedione exhibited uncompetitive kinetics in contrast to progesterone, a competitive inhibitor. No inhibition of microsomal electron transport enzyme activity was found, even at concentrations of pregnanolone greatly in excess of those required to inhibit drug metabolism. Pregnanolone and substrate (p-nitroanisole) produced individual, additive spectral changes with hepatic microsomes, indicative of separate binding sites. These results suggest that progesterone and/or certain of its metabolites may play a physiologic role in regulating hepatic drug metabolism.