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

Mahesh N. Samtani, Matthias Schwab, Peter W. Nathanielsz, William J. Jusko

Research output: Contribution to journalArticle

17 Scopus citations

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 languageEnglish (US)
Pages (from-to)2279-2292
Number of pages14
JournalPharmaceutical Research
Volume21
Issue number12
DOIs
StatePublished - Dec 1 2004
Externally publishedYes

Keywords

  • Corticosteroid
  • Fetus
  • p-glycoprotein
  • Pharmacokinetics
  • Pregnancy

ASJC Scopus subject areas

  • Biotechnology
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry
  • Pharmacology (medical)

Fingerprint Dive into the research topics of 'Area/moment and compartmental modeling of pharmacokinetics during pregnancy: Applications to maternal/fetal exposures to corticosteroids in sheep and rats'. Together they form a unique fingerprint.

  • Cite this