TRETINOIN - A REVIEW OF THE NONCLINICAL DEVELOPMENTAL TOXICOLOGY EXPERIENCE

Tretinoin has been thoroughly evaluated for its potential as an embryo fetal developmental toxicant. Oral tretinoin produces developmental an omalies in animal models; the minimal teratogenic dose is consistently 2.5 to 10 mg/kg. In contrast, topical application does not induce dev elopmental malformations in laboratory animals. A structurally related compound, isotretinoin, is a potent toxicant in humans and animals; t he lowest systemic dose that induces fetal anomalies varies more than 100-fold depending on the model. Oral isotretinoin is a more potent de velopmental toxicant than oral tretinoin in monkeys. Between-drug diff erences in the metabolism and transplacental transfer of the two retin oids account for the differences in toxicant potency. Pharmacokinetic studies reveal that absorption of tretinoin from the skin is poor and yields maternal plasma concentrations below the developmentally toxic threshold established after oral administration. Analysis of outcomes of developmental toxicology and pharmacokinetic studies suggests that the human risk of fetal anomalies is negligible after therapeutic appl ication of topical tretinoin.