Pharmacokinetics of Etretin and Etretinate during Long-Term Treatment of Psoriasis Patients

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Abstract
The aromatic retinoic acid derivative etretin has recently been introduced in the treatment of severe psoriasis and other dyskeratoses. Hitherto, the use of the carboxylic acid ester analogue, etretinate, has been hampered by an extremely long elimination half-life of up to 120 days for this drug. Seven patients of either sex from whom we recently reported single-dose pharmacokinetics have been studied after 1 and 3 months multiple dose administration of the drugs. Four were given etretin and three etretinate. Etretin, both as drug and as metabolite, was absorbed faster than etretinate as judged from t-lag, tm and t1/2ka. Etretin as drug was eliminated faster than the metabolite etretin, t1/2.beta. 2.39 .+-. 1.16 days compared to 6.51 .+-. 2.06 days. In patients receiving etretinate the terminal disposition or elimination half-lives for cis-etretin (t1/2.lambda.3 15.9 .+-. 9.9 days) were longer than for the metabolite etretin and exhibit a pronounced interindividual variation from 4.5 to 22.8 days. Similarly, cis-etretin accumulated very marked in comparison to the metabolite etretin of the drug etretinate. Assuming 40% systemic availability for both drugs, the central compartment of distribution constituted about 12-32% in case of etretin and about 0.8-3.6% in case of etretinate of the calculated apparent total volume of distribution at steady state, which showed mean values of 3.5 and 39.6 l .cntdot. kg .cntdot. -1, respectively, presumably reflecting the higher lipophilic nature of the latter compound.

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