THE AREA UNDER THE CONCENTRATION-TIME CURVE OF ALL-TRANS-RETINOIC ACID IS THE MOST SUITABLE PHARMACOKINETIC CORRELATE TO THE EMBRYOTOXICITYOF THIS RETINOID IN THE RAT

Earlier studies with etretinate and its metabolite acitretin suggested that area under the concentration-time curve (AUG) is the most suitab le pharmacokinetic correlate to etretinate-induced teratogenesis. In a n attempt to test this hypothesis with respect to the embryotoxic effe cts of all-trans-retinoic acid (all-trans-RA), we determined the embry otoxicity and plasma pharmacokinetics of all-trans-RA and its metaboli tes following administration of all-trans-RA to Wistar rats on Gestati onal Day (GD) 9, either subcutaneously (sc; dose levels 1, 3, or 5 mg/ kg body mass) or orally (po; 5 mg/kg body mass). The 5 mg/kg dose of a ll-trans-RA was not embryotoxic when administered orally but led to hi gh rates of embryolethality and skeletal defects following sc treatmen t. Determination of retinoids by HPLC showed that all-trans-RA reached similar maximum plasma concentrations (C-max) after both dosing regim ens, but its plasma AUC was ca threefold higher after sc injection tha n po administration due to the slower uptake rate of the drug and its limited detoxification via beta-glucuronidation following sc injection . Furthermore, retinoid analysis in rat tissues (liver, kidney, duoden um, and jejunum), collected 1 hr after sc or po administration of 5 mg all-trans-RA/kg body mass on GD 9, confirmed that formation of all-tr ans-retinoyl-beta-glucuronide was much more extensive after po than af ter sc administration. Finally, linear regression analysis of either C -max or AUC values of all-trans-RA in rat plasma and fetal abnormality rates showed that AUC values are better correlated with the embryotox ic outcome than C-max [AUC-based correlation coefficient (r) > 0.90; C -max-based r < 0.43]. Our findings establish the relevance of the AUC of all-trans-RA, and not its C-max, as the most appropriate pharmacoki netic marker of embryonic exposure and embryotoxic potency of all-tran s-RA and stress the importance of the duration of exposure as a major determinant of embryotoxic outcome for retinoids. (C) 1997 Academic Pr ess.