Clinical Pharmacokinetics of Tretinoin
Clinical Pharmacokinetics of Tretinoin
复制标题
维A酸的临床药代动力学
作者：
M. Regazzi;I. Iacona;Cristina Gervasutti;M. Lazzarino;S. Toma
摘要最近关于维甲酸（全反式维甲酸）在急性早幼粒细胞白血病（APL）患者中的显著抗肿瘤作用的报道，引起了人们对使用这种药物作为化学预防和治疗剂的极大兴趣。然而，维甲酸的生物学功效被（推测）药物的诱导性高钾化作用大大削弱，导致维甲酸敏感性和抗性降低。几项药代动力学研究表明，当药物以长期每日维甲酸方案给药时，血浆药物暴露[通过浓度-时间曲线下面积（AUC∞）测量]显著且迅速下降。这些观察结果导致了这样一种假设，即对维甲酸的获得性临床耐药性的迅速发展可能具有药理学基础，并且是由于在连续治疗过程中不能向白血病细胞提供有效的药物浓度所致。和（iii）诱导细胞质视黄酸结合蛋白（CRABP），其导致增加的药物螯合。最受欢迎的解释是，持续的维甲酸治疗通过细胞色素P450（CYP）酶诱导药物catalysts。几种旨在预防或克服诱导的维甲酸耐药性的策略已经并正在计划中。这些策略包括间歇给药、抗氧化酶药理学抑制剂给药、与干扰素-α联合给药以及维甲酸脂质体静脉给药。由于这些策略目前正在调查中，招募的患者数量很少，需要进一步的研究来确定这些新的药物给药方案的疗效和毒性，在本文中，我们提供了维甲酸生理学和药代动力学的相关方面的概述，并总结了目前的知识状况，以帮助更好地优化维甲酸管理。
SummaryRecent reports of the dramatic antitumour effect of tretinoin (all-trans retinoic acid) in patients with acute promyelocytic leukaemia (APL) have generated a great deal of interest in the use of this drug as a chemopreventive and therapeutic agent. However, the biological efficacy of tretinoin is greatly impaired by (presumably) an induced hypercatabolism of the drug leading to reduced tretinoin sensitivity and resistance.Several pharmacokinetic studies have shown that plasma drug exposure [as measured by the plasma area under the concentration-time curve (AUC∞)] declines substantially and rapidly when the drug is administered in a long term daily tretinoin regimen. These observations led to the hypothesis that the rapid development of acquired clinical resistance to tretinoin may have a pharmacological basis and result from an inability to present an effective drug concentration to the leukaemic cells during continuous treatment.The principal mechanisms proposed to explain the increased disappearance of tretinoin from plasma include: (i) decreased intestinal absorption; (ii) enhanced enzymatic catabolism; and (iii) the induction of cytoplasmic retinoic acid binding proteins (CRABP), which leads to increased drug sequestration. The most favoured explanation is that continuous tretinoin treatment acts to induce drug catabolism by cytochrome P450 (CYP) enzymes.Several strategies aimed at preventing or overcoming induced tretinoin resistance have been, and are being, planned. These strategies include intermittent dose administration, administration of pharmacological inhibitors of CYP oxidative enzymes, combination with interferon-α and intravenous administration of liposome-encapsulated tretinoin. As these strategies are now under investigation and the number of patients enrolled is small, further studies are needed to determine the efficacy and toxicity of these new schedules of drug administration.In this article we provide an overview of the relevant aspects of tretinoin physiology and pharmacokinetics, and summarise the current status of knowledge to help in the better optimisation of tretinoin administration.
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影响因子：
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作者：
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DOI：
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影响因子：
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DOI：
10.1042/bj2770527
发表时间：
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影响因子：
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DOI：
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