Transplacental pharmacokinetics of a synthetic retinoid which is not bound by mouse embryonic cellular retinoic acid-binding protein.
Teratogenicity is a major side effect of retinoids, a class of compounds used in dermatology and oncology. The binding of retinoids to cellular retinoic acid-binding protein (CRABP) has been suggested to be important for the mechanism of retinoid embryopathy. Here data are presented on the transplacental pharmacokinetics of CD394 (4-[3-(1-adamantyl)-4-methoxybenzamido] benzoic acid) which does not bind to murine embryonic CRABP, although it is active in rat whole embryo culture and teratogenic in the rabbit in vivo. A single intragastric dose of CD394 (10 mg/kg) was administered to mice on day 11 of gestation. The extent of placental transfer of CD394, determined by HPLC, resembled more that of 13-cis-retinoic acid which also does not bind to CRABP, than that of the CRABP-binding all-trans-retinoic acid. CMax values of CD394 obtained after 1-2 h were: 1368 +/- 652 ng/ml for plasma, 203 +/- 132 ng/g for embryo and 856 +/- 563 ng/g for placenta. AUC (area-under-the-concentration-time-curve) values (0-12 h) were: 4319 ng x h/ml for plasma, 751 ng x h/g for embryo and 3163 ng x h/g for placenta. Thus, CD394 reached the embryo, although embryonic AUC values were less than one fifth of the maternal plasma AUC values. CD394 did not alter endogenous retinol concentrations in plasma, embryo, yolk sac or placenta. Our results indicate that CD394 reaches the embryo in vivo without binding to CRABP, although embryonic concentrations stayed well below plasma levels. This supports the opinion that binding to embryonic CRABP is not a prerequisite for reaching effective embryo concentrations and for the teratogenicity of retinoids.
Sass
J O
JO
Institut für Toxikologie und Embryopharmakologie, Freie Universität Berlin, Germany.
Hartmann
J
J
Chahoud
I
I
Shroot
B
B
Nau
H
H
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D005260:Female; D008431:Maternal-Fetal Exchange; D051379:Mice; D008815:Mice, Inbred Strains; D011247:Pregnancy; D011485:Protein Binding; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D012176:Retinoids / Q000493:pharmacokinetics*; D013723:Teratogens / Q000493:pharmacokinetics*
C092136:CD 394; D018168:Receptors, Retinoic Acid; D012176:Retinoids; D013723:Teratogens; C082927:retinoic acid binding protein I, cellular; C082928:retinoic acid binding protein II, cellular