Abstract
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 μg kg-1 of a depot formulation. Additional data for betamethasone 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 Win-Nonlin 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.
Original language | English (US) |
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Pages (from-to) | 2279-2292 |
Number of pages | 14 |
Journal | Pharmaceutical Research |
Volume | 21 |
Issue number | 12 |
DOIs | |
State | Published - Dec 2004 |
Externally published | Yes |
Keywords
- Corticosteroid
- Fetus
- Pharmacokinetics
- Pregnancy
- p-glycoprotein
ASJC Scopus subject areas
- Biotechnology
- Molecular Medicine
- Pharmacology
- Pharmaceutical Science
- Organic Chemistry
- Pharmacology (medical)