Area/moment and compartmental modeling of pharmacokinetics during pregnancy: applications to maternal/fetal exposures to corticosteroids in sheep and rats.
OBJECTIVE
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.
Samtani
Mahesh N
MN
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, New York 14260, USA.
Schwab
Matthias
M
Nathanielsz
Peter W
PW
Jusko
William J
WJ
D000818:Animals; D001623:Betamethasone / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D003907:Dexamethasone / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D008431:Maternal-Fetal Exchange / Q000502:physiology*; D008954:Models, Biological; D008956:Models, Chemical; D015233:Models, Statistical; D011247:Pregnancy; D051381:Rats; D012756:Sheep
D003907:Dexamethasone; D001623:Betamethasone