Percutaneous retinoid absorption and embryotoxicity.
A single application of 17 micrograms/kg or 8.7 mg/kg all-trans-[10,11-3H2]-retinoic acid dissolved in acetone to shaved dorsal hamster skin resulted in rapid absorption and dose-dependent rates of elimination. An equation describing a two-compartment open model with a very brief lag time and first-order uptake and elimination was used to describe the central plasma compartment kinetics. Unchanged all-trans-retinoic acid represented less than or equal to 4% of the total circulating radio-activity. Peak circulating concentrations of parent all-trans-retinoic acid were less than those observed after an equivalent oral dose, but prolonged absorption from the skin appears to contribute to high total bioavailability of topical retinoid. Topical administration to intact skin of up to three consecutive doses of 10.5 mg/kg/d all-trans-retinoic acid or a single 5 mg/kg dose of etretinate (Ro 10-9359) during a critical stage of embryogenesis in hamsters caused erythema and/or dose-dependent epidermal hyperplasia at the site of application, but failed to induce a significant teratogenic response. Topical application of 0.01-1.0 mg/kg arotinoid Ro 13-6298 resulted in dose-dependent mucocutaneous toxicity and an increase in the numbers of dead embryos and malformed offspring. The marked skin toxicity and attenuated concentrations in maternal blood, compared to the oral route, limit the amounts of retinoid that can reach the hamster embryo. It is thus more important to compare the retinoid systemic values (absorbed dose) than it is to compare the oral or topical (applied) dose, when interpreting the results of conventional teratogenicity bioassays. The data suggest that in the human it is skin toxicity that limits the amounts of retinoid that can be applied and subsequently reach the embryo. In the rodent, overt skin toxicity under continued dosing could increase the amounts of retinoid penetrating the skin and reaching the embryo.
Willhite
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CC
Department of Health Services, State of California, Berkeley.
Sharma
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RP
Allen
P V
PV
Berry
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DL
D000284:Administration, Oral; D000287:Administration, Topical; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D001565:Benzoates / Q000633:toxicity; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian / Q000187:drug effects* / Q000502:physiology; D005050:Etretinate / Q000633:toxicity; D005260:Female; D008431:Maternal-Fetal Exchange / Q000502:physiology; D008647:Mesocricetus; D011247:Pregnancy; D012176:Retinoids / Q000633:toxicity; D012867:Skin / Q000187:drug effects / Q000378:metabolism; D012869:Skin Absorption / Q000187:drug effects*; D012879:Skin Physiological Phenomena; D014212:Tretinoin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity
D000970:Antineoplastic Agents; D001565:Benzoates; D012176:Retinoids; D014212:Tretinoin; D005050:Etretinate; C034814:ethyl-p-((E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propenyl)benzoic acid