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

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9-Cis-retinoic acid (9-cis-RA) has been proposed to be the endogenous ligand of retinoid X receptors. We examined the plasma pharmacokinetics of 9- cis-RA and its metabolites in nonpregnant female NMRI mice after oral dosing with 50 mg 9-cis-RA/kg body weight. Furthermore, we studied the metabolism of 9-cis-RA and its transfer to the embryo following oral administration of the precursor 9-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 levels of 9-cis-RA reached their maximum within 40- 60 min and then declined 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; among them, the β-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 metabolite 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 were similarly 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 could be identified as 9,13-dicis-RA by the following methods: coelution with 9,13-dicis-RA reference compound in various HPLC systems both before and after derivatization; comparison of its UV spectrum with that of the reference compound; and comparison of its mass spectrum with that of the reference compound using HPLC/MS. Two hr after 9-cis-RAL administration, 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 the 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) suggest 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 transplacental 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 limited placental transfer to the mouse and rat embryos.

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