Nulman I, Berkovitch M, Klein J, Pastuszak A, Lester R S, Shear N, Koren G
Department of Pediatrics and Research Institute, The Hospital for Sick Children, Toronto, The University of Toronto, Ontario, Canada.
J Clin Pharmacol. 1998 Oct;38(10):926-30. doi: 10.1002/j.1552-4604.1998.tb04388.x.
Isotretinoin is the most potent human teratogen on the market. Women for whom contraception fails may conceive during or soon after discontinuing isotretinoin therapy, making its elimination kinetics a crucial determinant of fetal safety. The steady-state pharmacokinetics of isotretinoin and its major 4-oxo metabolite were studied in 16 adult patients treated for acne who were receiving doses that ranged from 0.47 to 1.7 mg/kg daily. This is the first study of the pharmacokinetics of isotretinoin in women of childbearing age (n = 11). The clinical efficacy and tolerability of isotretinoin was investigated, and the correlation between these data and steady-state serum concentrations of isotretinoin was tested. The concentration-time data best fitted a two-compartment open model with linear elimination. There was no correlation between efficacy and tolerability of isotretinoin and steady-state serum concentrations. There was no correlation between dose of isotretinoin and steady-state concentration, due to the large variability in apparent clearance. Values for elimination half-life (t1/2) of isotretinoin and its metabolite were 29+/-40 hours and 22+/-10 hours, respectively. These data suggest a longer elimination t1/2 of the parent drug than previously reported. This is probably due to the longer sampling time used in this study (as long as 28 days). This study suggests that a greater variability exists in the safe time after discontinuation of the drug for onset of conception.
异维甲酸是市面上最具致畸性的药物。避孕失败的女性在停用异维甲酸治疗期间或之后不久可能怀孕，因此其消除动力学是胎儿安全的关键决定因素。在16名接受痤疮治疗的成年患者中研究了异维甲酸及其主要4-氧代代谢物的稳态药代动力学，这些患者每日接受的剂量范围为0.47至1.7mg/kg。这是首次对育龄女性（n = 11）的异维甲酸药代动力学进行研究。研究了异维甲酸的临床疗效和耐受性，并测试了这些数据与异维甲酸稳态血清浓度之间的相关性。浓度-时间数据最符合具有线性消除的二室开放模型。异维甲酸的疗效和耐受性与稳态血清浓度之间没有相关性。由于表观清除率差异很大，异维甲酸剂量与稳态浓度之间没有相关性。异维甲酸及其代谢物的消除半衰期（t1/2）值分别为29±40小时和22±10小时。这些数据表明母体药物的消除t1/2比先前报道的更长。这可能是由于本研究中使用的采样时间更长（长达28天）。这项研究表明，停药后受孕的安全时间存在更大的变异性。
