SINGLE VERSUS MULTIPLE-DOSE ADMINISTRATION OF ALL-TRANS-RETINOIC ACIDDURING ORGANOGENESIS - DIFFERENTIAL METABOLISM AND TRANSPLACENTAL KINETICS IN RAT AND RABBIT

Standard teratogenicity testing is usually performed by administration of a test compound daily throughout an extended period of organogenes is (e.g., between Days 6 and 15 in rat and 6 and 18 in rabbit). On the other hand, single dose experiments during a specific period were oft en demonstrated to be more effective in unveiling a particular teratog enic effect. We have assessed here if toxicokinetics is an important f actor for the interpretation of the differences between two administra tion regimens of all-trans-retinoic acid (all-trans-RA) in two species . The transplacental pharmacokinetics of a low teratogenic dose of all -trans-RA administered orally were compared in a single versus multipl e dose regimen in both the Wistar rat and the Swiss hare rabbit. In bo th species, the single dose animals were treated on Gestational Day 12 , while the multiple dose animals received daily doses from Gestationa l Days 7 through 12. Pharmacokinetic profiles were determined for mate rnal plasma and embryo after dosing on Gestational Day 12(for both the single and multiple dose regimens) and analyzed by reverse-phase HPLC . The dose used for both species was 6 mg/kg body wt/day which has rec ently been reported to be a marginal to low teratogenic dose when admi nistered daily throughout organogenesis. In both rat and rabbit, the A UC of all-trans-retinoic acid in maternal plasma was much reduced (fac tor of 9 in the rat, factor of 2 in the rabbit) after multiple applica tion as compared to the single administration, presumably due to enzym e induction. A similar, but not as pronounced effect was also observed in the embryo of both species. This diminished effect in the embryo i ndicates a relative increase of placental transfer at the lower matern al plasma concentration observed after multiple dosing, which may poss ibly bd due to an increased availability of binding sites such as cyto solic retinoic acid binding protein and nuclear receptors in the embry o. In the rat, also the metabolite levels were reduced, while in the r abbit, the metabolites of the 13-cis-configuration were concomitantly increased. Our results suggest that multiple administration of a drug such as retinoic acid, which induces its own elimination pathways, res ults in substantially lowered drug levels in maternal plasma and embry o. In such cases, single doses administered at specific developmental periods are expected to be more effective in uncovering particular dev elopmental effects. (C) 1995 Academic Press, Inc.