Teratogenicity of the 13-cis and all-trans-isomers of the aromatic retinoid etretin: correlation to transplacental pharmacokinetics in mice during organogenesis after a single oral dose.
NMRI mice were treated on day 11 (day 0 = plug day) of gestation with a single oral dose of 100 mg/kg of either all-trans-etretin (acitretin) or 13-cis-etretin. For teratology studies mice were sacrificed on day 18 of gestation, and the fetuses were examined for malformations. For pharmacokinetic studies, groups of 5 mice were sacrificed after 5, 10, and 30 min and 1, 2, 4, and 8 h. The concentrations of retinoids in maternal plasma and in embryos were determined by a newly developed HPLC gradient method. All-trans-etretin induced malformations in 94% of the fetuses, mainly in fore and hind limbs and cleft palate. 13-cis-etretin did not show any teratogenic or embryo-lethal effects at the dose level used. These findings could be explained by a transplacental pharmacokinetic study. The maximum peak level and also the AUC (area under the concentration-time curve) value of all-trans-etretin in the embryos was 7-8 times higher than corresponding values for 13-cis-etretin, probably due to extensive transport of the trans-isomer and limited transport of the cis-isomer from maternal plasma to the embryos. The concentration quotient between embryo and the maternal plasma was between 0.43 and 1.10 for all-trans-etretin, and only 0.16-0.31 for 13-cis-etretin over the time period studied. An in vivo isomerization of the compounds was also observed which was more extensive for 13-cis-etretin than for all-trans-etretin. Our results indicate that the low teratogenic potency of 13-cis-etretin is due to a limited placental transfer of this compound; on the other hand, the potent teratogen all-trans-etretin is rapidly and extensively transferred to the embryo.
Löfberg
B
B
Institute for Toxicology and Embryopharmacology, Free University Berlin, Federal Republic of Germany.
Chahoud
I
I
Bochert
G
G
Nau
H
H
D000014:Abnormalities, Drug-Induced / Q000209:etiology*; D017255:Acitretin; D000818:Animals; D001842:Bone and Bones / Q000002:abnormalities*; D003879:Dermatologic Agents / Q000633:toxicity*; D005260:Female; D007641:Keratolytic Agents / Q000493:pharmacokinetics / Q000633:toxicity*; D008431:Maternal-Fetal Exchange / Q000502:physiology; D051379:Mice; D008815:Mice, Inbred Strains; D011247:Pregnancy; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014212:Tretinoin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity
D003879:Dermatologic Agents; D007641:Keratolytic Agents; D014212:Tretinoin; D017255:Acitretin