Larsen F G, Jakobsen P, Larsen C G, Kragballe K, Nielsen-Kudsk F
Department of Dermatology, Marselisborg Hospital, Aarhus, Denmark.
Pharmacol Toxicol. 1988 Mar;62(3):159-65. doi: 10.1111/j.1600-0773.1988.tb01865.x.
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 t 1/2 ka. Etretin as drug was eliminated faster than the metabolite etretin, t 1/2 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 cisetretin (t 1/2 lambda 3 15.9 +/- 9.9 days) were longer than for the metabolite etretin and exhibit a pronounced interindividual variation from 4.25 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 1.kg.-1, respectively, presumably reflecting the higher lipophilic nature of the latter compound.
芳香维甲酸衍生物依曲替酯最近已被用于治疗重度银屑病和其他角化异常疾病。迄今为止，羧酸酯类似物依曲替酸的使用受到该药物长达120天的极长消除半衰期的限制。我们最近报道了单剂量药代动力学的7名患者，在多次给药1个月和3个月后对其进行了研究。4名患者服用依曲替酯，3名患者服用依曲替酸。从达峰时、达峰时间和吸收半衰期判断，依曲替酯作为药物及其代谢产物的吸收速度比依曲替酸快。依曲替酯作为药物的消除速度比代谢产物依曲替酯快，消除半衰期分别为2.39±1.16天和6.51±2.06天。在接受依曲替酸的患者中，顺式维甲酸的终末处置或消除半衰期（15.9±9.9天）比代谢产物依曲替酯长，个体间差异显著，为4.25至22.8天。同样，与依曲替酸的代谢产物依曲替酯相比，顺式维甲酸的蓄积非常明显。假设两种药物的全身利用率均为40%，依曲替酯的中央分布室在稳态时占计算出的表观总体分布容积的12%-32%，依曲替酸则为0.8%-3.6%，其平均值分别为3.5和39.6升/千克，这可能反映了后一种化合物更高的亲脂性。
