Pharmacokinetic aspects of drug effects in vitro (II) placental transfer to the embryo and activity of some carboxylic acids structurally related to valproic acid in whole embryos in culture.
The transfer of a group of short/medium chain-length carboxylic acids, related to the antiepileptic drug valproic acid (VPA), to the whole rat embryo in vitro was investigated. The protein binding of the drugs in the culture medium determined the placental transfer in vitro: at comparable total concentrations, the substances that bound to a lesser degree (VPA and its metabolite 2-propyl-4-pentenoic acid; 4-en-VPA) reached higher embryonic levels than the more highly bound substances, octanoic acid (OA), 2-methyl-2-ethylcaproic acid (MEC), and the VPA metabolite, 2-propyl-2-pentenoic acid (2-en-VPA). Consequently, the amount of drug added to the culture did not correlate with the transfer to the embryo, but the concentration of the free drug in the culture medium correlated highly with embryonic exposure. The concentration of the drugs in the cultured embryos, the embryonic membranes and the subembryonic fluid were higher than the corresponding free concentrations in the medium. The difference in the teratogenic potency of the substances tested was clearly related to their intrinsic activity, since even high embryonic concentrations of 2-en-VPA, MEC and OA did not produce adverse effects in contrast to VPA and 4-en-VPA which were effective at levels several-fold lower. The effective concentrations of VPA in the cultured embryos were almost ten times lower than those in embryos in vivo. The factors responsible for the high vulnerability of the cultured embryos to the action of VPA are as yet unknown. Our results indicate that the determination of drug concentrations in cultured embryonic tissue is imperative for a rational interpretation of experimental data obtained from in vitro studies; a full validation of in vitro systems must incorporate pharmacokinetic studies.
Nau
H
H
Institute of Toxicology and Embryopharmacology, Free University Berlin, Garystrasse 5, D-1000 Berlin 33, Federal Republic of Germany.
Lewandowski
C
C
Klug
S
S
Neubert
D
D