Teratogenicity of steady-state concentrations of etretinate and metabolite acitretin maintained in maternal plasma and embryo by intragastric infusion during organogenesis in the mouse: a possible model for the extended elimination phase in human therapy.
Etretinate (Tegison, Tigason), a retinoid used for the treatment of skin disorders such as psoriasis, was shown to teratogenic in the human. Because of the long terminal half-life of this drug (100 days), considerable plasma levels of etretinate and its main metabolite, etretin (acitretin), were observed for up to 2 years following discontinuation of therapy. We have therefore investigated, in a newly developed animal model, the potential teratogenic risk of such persisting levels of these aromatic retinoids. Etretinate was administered by intragastric infusion throughout organogenesis in the mouse (day 8-15) via subcutaneously implanted osmotic minipumps connected to external reservoirs containing oily solutions of the drug. Dose-dependent developmental effects were found, the fetal weight decreased and the resorption rate and incidence of major malformation increased. A dose of 0.84 mg/kg/day resulted in retinoid-specific defects, in particular shortening of the limbs and cleft palate. This low dose infused resulted in mean etretinate concentrations of 6.5 ng/ml maternal plasma and 12.5 ng/g embryo (measured on days 10 and 12 of gestation). The corresponding concentrations of the metabolite etretin were 38 ng/ml plasma and 95 ng/g embryo. Our results emphasize the high teratogenic risk of relatively low, persisting concentrations of etretinate and etretin such as those observed after discontinuation of human therapy, because the area of the concentration-time curve is likely to be the decisive parameter in regard to teratogenesis.
Löfberg
B
B
Institute of Toxicology and Embryopharmacology, Free University Berlin.
Reiners
J
J
Spielmann
H
H
Nau
H
H
D000014:Abnormalities, Drug-Induced / Q000209:etiology*; D017255:Acitretin; D000818:Animals; D005314:Embryonic and Fetal Development / Q000187:drug effects*; D005050:Etretinate / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D005260:Female; D015918:Infusion Pumps, Implantable; D008431:Maternal-Fetal Exchange; D051379:Mice; D008954:Models, Biological; D011247:Pregnancy; D014212:Tretinoin / Q000031:analogs & derivatives* / Q000097:blood
D014212:Tretinoin; D005050:Etretinate; D017255:Acitretin