ALL-TRANS-RETINOIC ACID IN MATERNAL PLASMA AND TERATOGENICITY IN RATSAND RABBITS

Citation
Ea. Tembe et al., ALL-TRANS-RETINOIC ACID IN MATERNAL PLASMA AND TERATOGENICITY IN RATSAND RABBITS, Toxicology and applied pharmacology, 141(2), 1996, pp. 456-472
Citations number
55
Categorie Soggetti
Pharmacology & Pharmacy",Toxicology
ISSN journal
0041008X
Volume
141
Issue
2
Year of publication
1996
Pages
456 - 472
Database
ISI
SICI code
0041-008X(1996)141:2<456:AAIMPA>2.0.ZU;2-F
Abstract
The teratogenicity of all-trans-retinoic acid, 13-cis-retinoic acid, a nd retinol was investigated in pregnant Wistar rats given a single ora l dose on Day 10 of gestation. External malformations showed dose-depe ndent increases and the order of potency was all-trans-retinoic acid > retinol > 13-cis-retinoic acid. The metabolites in maternal plasma we re determined following a single oral dose on Day 10 of gestation. Equ ipotent teratogenic doses of all-trans-retinoic acid and 13-cis-retino ic acid had similar plasma levels of all-trans-retinoic acid; however, retinol teratogenicity could not be accounted for by circulating all- trans-retinoic acid or its metabolites. The teratogenicity and materna l pharmacokinetics of all-trans-retinoic were compared in pregnant Wis tar rats when given as a single dose (50 mg/kg) and as three equal dos es (16.66 mg/kg) over 6 hr. Divided doses a ere of slightly greater po tency than the single dose but the maximum observed concentration (C-m ax) and area under the plasma concentration-time curve (AUG) values fo r the second and third doses were greatly attenuated compared with the first dose; in consequence, both the total AUC and C-max were reduced compared with the single dose. The altered profile could not be expla ined by increased formation of all-trans-retinoic acid glucuronide or increased isomerisation to 13-cis-retinoic acid. The maternal plasma l evels of all-trans-retinoic acid in pregnant rabbits were reduced by a dose given 24 hr earlier. These data show that all-trans-retinoic aci d in maternal plasma is a poor indicator of fetal exposure to teratoge nic risk. (C) 1996 Academic Press, Inc.