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 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 beta-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 weeesimilarly high as those of 9-cis-RA.(ABSTRACT TRUNCATED AT 250 WORDS)
Tzimas
G
G
Institut für Toxikologie und Embryopharmakologie, Freie Universität Berlin, Germany.
Sass
J O
JO
Wittfoht
W
W
Elmazar
M M
MM
Ehlers
K
K
Nau
H
H
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004622:Embryo, Mammalian / Q000378:metabolism*; D005260:Female; D008431:Maternal-Fetal Exchange; D051379:Mice; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D014212:Tretinoin / Q000378:metabolism*
D014212:Tretinoin