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
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.