394 INCREASED CLEARANCE OF PHENYTOIN (PH) IN PREGNANCY IS DUE TO MTERNAL NOT PETAL OR PLACENTAL, METABOLISM

Abstract

Clearance of Phenytoin (PH) increases during pregnancy (Lander et al. Eur. J. Clin. Pharm. 1984), but the sites of its apparently enhanced metabolism and the mechanisms responsible are unknown. We have observed decreased maternal clearance of PH within a few hours of delivery suggesting that products of conception either participate directly in metabolism of PH or stimulate maternal systems. To approach this problem, we estimated fetal contributions to PH metabolism by following disappearance of transplacentally acquired drug in 9 neonates born to women whose PH requirements had increased during pregnancy and compared in vitro metabolism of PH by placentas from treated (N=2) and non-treated (N=5) women with that of rat hepatic microsomes. In the first 18 to 24 hours following delivery, plasma PH levels decreased by only 10-50% in non-breast fed neonates indicating that increased clearance of drug during pregnancy could not be accounted for by fetal metabolism. While oxidation of PH was detectable in reaction mixtures incubated for 30 to 60 min with rat liver microsomes, no metabolites could be detected following incubations up to 14 hours with either placental homogenates or postmitochondrial supernatants. These results suggest that products of conception do not participate significantly in PH metabolites during pregnancy. Rather it appears that a factor(s) produced by the fetal-placental unit directly stimulates maternal metabolic pathways.