Comparison of in vitro and in vivo developmental toxicity and pharmacokinetics of phenytoin in the rat.
The rat whole embryo culture was compared to an in vivo experiment with regard to embryotoxicity as well as exposure characteristics, using phenytoin as a model compound. Intra-embryonic concentrations and their embryotoxic effects were determined on gestation day 11 after in vitro administration of 50-150 microg/ml or in vivo gavage of 500-1500 mg/kg body-weight on gestation day 10. In addition, exposure kinetics were studied in vivo after a single oral dose on gestation day 10, and developmental defects on gestation day 21 were scored. The embryotoxic effects observed on gestation day 11 were more pronounced after in vitro exposure in comparison to in vivo exposure at similar intra-embryonic concentrations. Exposure of phenytoin on gestation day 10 in vitro via the culture medium resulted in general embryotoxicity on gestation day 11, whereas in vivo effects as determined on gestation day 11 were minimal. Plasma concentrations of phenytoin increased and plateaued around 35 microg/ml during the 48 hr monitoring period. Plasma concentration curves and pharmacokinetic parameters did not show remarkable differences between the dose groups, indicating that absorption is the limiting factor at the dose range used. Although the developmental effects were minimal as observed in vivo on gestation day 11, specific malformations (defects encompassing the urogenital. craniofacial and skeletal systems) were observed on gestation day 21. These findings show that with similar intra-embryonic concentrations of phenytoin the embryotoxicity in rat whole embryo culture was not comparable with the in vivo embryotoxicity as determined on gestation day 11. This discrepancy may at least partly be explained by differences in exposure characteristics.
Beekhuijzen
M E
ME
Laboratories for Health Effects Research, National Institute for Public Health and the Environment, Bilthoven, The Netherlands.
Verhoef
A
A
Klaassen
R
R
Rompelberg
C J
CJ
Piersma
A H
AH
D000014:Abnormalities, Drug-Induced / Q000473:pathology; D000284:Administration, Oral; D000704:Analysis of Variance; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005314:Embryonic and Fetal Development / Q000187:drug effects*; D005260:Female; D005865:Gestational Age; D008431:Maternal-Fetal Exchange; D010672:Phenytoin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D011247:Pregnancy; D051381:Rats; D013723:Teratogens / Q000493:pharmacokinetics / Q000633:toxicity
D000927:Anticonvulsants; D013723:Teratogens; D010672:Phenytoin