Isotretinoin (13-cis-retinoic acid) metabolism, cis-trans isomerization, glucuronidation, and transfer to the mouse embryo: consequences for teratogenicity.
It has been reported that fractionated doses of 13-cis-retinoic acid are disproportionately more embryotoxic in pregnant mice than is the same dose given in a single bolus. Here, we examined limited pharmacokinetic profiles of a single (100 mg/kg dose given to NMRI mice on day 11 of gestation) versus multiple (3 x 100 mg/kg, 4 h apart) doses in an effort to assess the relative contribution to teratogenicity made by the drug and/or its metabolites. The major plasma metabolite of 13-cis-retinoic acid in the mouse was 13-cis-retinoyl-beta-glucuronide, followed by the 4-oxo metabolites and all-trans-retinoic acid. Transfer to the mouse embryo was very efficient for all-trans-retinoic acid, whereas, it was tenfold less efficient for 13-cis-retinoic acid and 100-fold less efficient for 13-cis-retinoyl-beta-glucuronide. The isomer all-trans-retinoic acid was found in the placenta at concentrations two- to three-fold higher than in the plasma, suggesting placental accumulation as well as placental cis/trans isomerization. Since 13-cis-retinoyl-beta-glucuronide and 13-cis- and all-trans-retinoic acid were detected in the embryo after this multiple dosing schedule, any of the three or their combinations may have been involved in the induction of malformations, but all-trans-retinoic acid, a well-known potent teratogen detected at concentrations of between 590 and 80 ng/g for 10 critical hours during gestation, could have been the major component.
Creech Kraft
J
J
Institute of Toxicology and Embryopharmacology, Free University Berlin, Federal Republic of Germany.
Eckhoff
C
C
Kochhar
D M
DM
Bochert
G
G
Chahoud
I
I
Nau
H
H
D000284:Administration, Oral; D000818:Animals; D001842:Bone and Bones / Q000002:abnormalities / Q000187:drug effects; D004334:Drug Administration Schedule; D004622:Embryo, Mammalian / Q000187:drug effects*; D005260:Female; D005865:Gestational Age; D005965:Glucuronates / Q000097:blood / Q000378:metabolism*; D015474:Isotretinoin / Q000493:pharmacokinetics*; D008431:Maternal-Fetal Exchange / Q000187:drug effects; D051379:Mice; D008815:Mice, Inbred Strains; D010920:Placenta / Q000737:chemistry / Q000187:drug effects; D011247:Pregnancy; D013237:Stereoisomerism; D013723:Teratogens; D014212:Tretinoin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity
D005965:Glucuronates; D013723:Teratogens; C026787:retinoyl glucuronide; D014212:Tretinoin; D015474:Isotretinoin