Teratogenicity and transplacental pharmacokinetics of 13-cis-retinoic acid in rabbits.
No embryotoxic or teratogenic effects, considered to be treatment related, were observed in rabbits after daily oral doses of 3 mg/kg of 13-cis-retinoic acid (13-cis-RA) from Day 8 to Day 11 of gestation. In contrast, treatment with 15 mg/kg/day significantly increased the rate of fetal resorptions (22%) and 13 out of 68 surviving fetuses (16%) were malformed. Pharmacokinetic studies with both dosing regimens of 13-cis-RA in pregnant rabbits showed that on Day 11 of gestation, high concentrations of parent compound, 13-cis-RA, and its major metabolite, 13-cis-4-oxoRA, existed in maternal plasma. Much lower concentrations were found for all-trans-4-oxoRA and all-trans-RA. The area under the concentration-time curve (AUC) of all-trans-RA following the 15 mg/kg/day dosing regimen of 13-cis-RA was only 1.2% that of parent compound 13-cis-RA. At this dose, embryo levels of 13-cis-RA, 13-cis-4-oxoRA, and all-trans-4-oxoRA were 2.5-, 4.7-, and 3.6-fold higher by AUC comparison (24-hr period of Day 11) compared with the dose of 3 mg/kg. However, embryo levels of all-trans-RA were virtually identical at both doses and were, in fact, somewhat lower than endogenous concentrations measured in untreated rabbit embryos. In contrast to mice, where isomerization from 13-cis- to all-trans-RA was suggested to be crucial for the teratogenic action of 13-cis-RA, we found that the teratogenic action of 13-cis-RA (15 mg/kg/day) in rabbits is characterized by increased whole embryo concentrations of 13-cis-RA, 13-cis-4-oxoRA, and all-trans-4-oxoRA, but not of all-trans-RA.
Eckhoff
C
C
Department of Preclinical Dermatology Research, Hoffmann-La Roche Inc., Nutley, New Jersey 07110.
Chari
S
S
Kromka
M
M
Staudner
H
H
Juhasz
L
L
Rudiger
H
H
Agnish
N
N
D000014:Abnormalities, Drug-Induced / Q000209:etiology*; D000284:Administration, Oral; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian / Q000378:metabolism; D005260:Female; D005333:Fetus / Q000002:abnormalities / Q000187:drug effects*; D005865:Gestational Age; D015474:Isotretinoin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D008431:Maternal-Fetal Exchange; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D011817:Rabbits; D013237:Stereoisomerism; D014212:Tretinoin / Q000031:analogs & derivatives / Q000378:metabolism
C002202:4-oxoretinoic acid; D014212:Tretinoin; D015474:Isotretinoin