Area/moment and compartmental modeling of pharmacokinetics during pregnancy: applications to maternal/fetal exposures to corticosteroids in sheep and rats.

摘要

PURPOSE: The pharmacokinetics of corticosteroids in pregnancy were analyzed to assess maternal/fetal disposition and factors controlling fetal exposure. Area/Moment equations and compartmental models for estimating pharmacokinetic parameters from single dose data during pregnancy were developed. METHODS: Betamethasone in the maternal/fetal circulations of sheep was measured by HPLC after maternal intramuscular injection (n = 4) of 170 microg kg(-1) of a depot formulation. Additional data for beta-methasone in sheep and dexamethasone pharmacokinetics in rats were obtained from the literature. Area/Moment equations were derived using mass balance concepts, statistical moments, and Laplace theory. Area/Moment analysis, compartmental modeling, and allometric scaling to man for betamethasone were performed using WinNonlin and ADAPT II programs. RESULTS: Polyexponential maternal/fetal profiles for corticosteroids were observed. Clearance terms for corticosteroid transfer from fetus to mother were 4-fold higher than the clearance term for transfer in the opposite direction. A placental efflux process may restrict fetal access of corticosteroids which are known PGP substrates. The elimination clearance estimates indicate that fetal metabolism plays a minor role in corticosteroid elimination. CONCLUSIONS: Generalized and specific models for maternal/fetal pharmacokinetics were developed. An efflux transport mechanism, such as the known placental expression of PGP, could explain the limited fetal exposure of corticosteroids.