IDENTIFICATION OF 9,13-DICIS-RETINOIC ACID AS A MAJOR PLASMA METABOLITE OF 9-CIS-RETINOIC ACID AND LIMITED TRANSFER OF 9-CIS-RETINOIC ACID AND 9,13-DICIS-RETINOIC ACID TO THE MOUSE AND RAT EMBRYOS

9-Cis-retinoic acid (9-cis-RA) has been proposed to be the endogenous ligand of retinoid X receptors. We examined the plasma pharmacokinetic s of 9-cis-RA and its metabolites in nonpregnant female NMRI mice afte r oral dosing with 50 mg 9-cis-RA/kg body weight. Furthermore, we stud ied the metabolism of 9-cis-RA and its transfer to the embryo followin g oral administration of the precursor O-cis-retinaldehyde (9-cis-RAL; 100 mg/kg body weight) to pregnant mice and rats on gestational days 11 and 13, respectively. Following 9-cis-RA administration, plasma lev els of 9-cis-RA reached their maximum within 40-60 min and then declin ed in a monoexponential manner with an apparent half-life of 64 +/- 32 min. A great variety of polar metabolites of 9-cis-RA was found; amon g them, the B-glucuronides of 9-cis-RA (9-cis-RAG) and of 9-cis-4-oxo- RA (9-cis-4-oxo-RAG) could be identified. A further prominent polar me tabolite of 9-cis-RA in mouse plasma was shown to be an additional RA isomer (distinct from 13-cis-RA and all-trans-RA) whose concentrations weeesimilarly high as those of 9-cis-RA. This retinoid was also found in plasma of mice and rats after administration of 9-cis-RAL and coul d be identified as 9,13-dicis-RA by the following methods: co-elution with 9,13-dicis-RA reference compound in various HPLC systems both bef ore and after derivatization; comparison of its UV spectrum with that of the reference compound; and comparison of its mass spectrum with th at of the reference compound using HPLC/ MS. Two hr after 9-cis-RAL ad ministration, plasma levels of 9,13-dicis-RA greatly exceeded those of 9-cis-RA in both species. The biotransformation of 9-cis-RAL to 9-cis -RA and the further metabolism of the latter were more pronounced in t he mouse than in the rat. Two hr after administration of 9-cis-RAL, 9- cis-RA, 9,13-dicis-RA, and all-trans-RA were also found in the embryo. Ratios of embryonic to maternal plasma concentrations (E/M ratio) sug gest a limited placental transfer of 9-cis-RA to mouse and rat embryo (E/M ratios: 0.15 and 0.14, respectively). The extent of transplacenta l passage of 9,13 dicis-RA and 9-cis-RAG was even lower (E/M ratios: 0 .01-0.03 for 9,13-dicis-RA; 0.03 for 9-cis-RAG only in the mouse). Our study demonstrates that 9,13-dicis-RA is a major plasma metabolite of 9-cis-RA and that 9-cis-RA, 9,13-dicis-RA, and 9-cis-RAG show a limit ed placental transfer to the mouse and rat embryos.