Rigas J R, Francis P A, Muindi J R, Kris M G, Huselton C, DeGrazia F, Orazem J P, Young C W, Warrell R P
Department of Medicine, Memorial Sloan-Kettering Cancer Center, Cornell University Medical College, New York, N.Y. 10021.
J Natl Cancer Inst. 1993 Dec 1;85(23):1921-6. doi: 10.1093/jnci/85.23.1921.
All-trans-retinoic acid (all-trans RA) induces complete remission in most patients with acute promyelocytic leukemia (APL). However, continuous oral dosing results in progressive decline in plasma drug concentrations, which is associated with relapse and resistance to this retinoid. We speculated that the decline in drug levels, indicating acquired resistance, resulted partly from inducible cytochrome-P450 oxidative enzymes, which can catabolize all-trans RA.
We studied the clinical pharmacology of all-trans RA in cancer patients to determine possible mechanisms of acquired resistance and evaluated the potential for reversal by ketoconazole, an inhibitor of cytochrome-P450 oxidative enzymes.
Serial plasma samples were obtained from 54 patients with APL or advanced lung cancer after a single oral dose of all-trans RA (45 mg/m2). In the 34 patients with advanced lung cancer, all-trans RA (45 mg/m2) was administered twice daily for 4 weeks, and, on days 2, 28, and 29, serial plasma samples were again obtained after a single 45-mg/m2 dose. One hour prior to drug administration on days 2 and 29, a single oral dose (200-1200 mg) of ketoconazole was administered. Endogenous plasma concentrations of all-trans RA and 13-cis-retinoic acid were measured in a subset of these patients and in 11 with early-stage lung cancer.
The mean area under the curve for plasma drug concentration times time (AUC) for all-trans RA on day 1 varied substantially among patients. Compared with patients with APL, the 28 patients with advanced lung cancer who completed therapy demonstrated significantly lower AUC levels on day 1 (P = .06); a subgroup with levels less than 300 ng/mL per hour on day 1 had lower endogenous plasma all-trans RA concentrations than patients with APL or early-stage lung cancer or 14 normal subjects. Following continuous oral treatment, the mean day 28 AUC for all-trans RA was significantly lower than that on day 1 (213 ng/mL per hour versus 467 ng/mL per hour; P < .01), a decline significantly attenuated by ketoconazole, which increased the mean plasma all-trans RA AUC on day 29 to 375 ng/mL per hour (P < .01).
Reported variability for the pharmacokinetics of all-trans RA may result from disease-related or population-based differences in basal catabolic rates influenced by genetic or environmental factors. However, the pattern of inducible catabolism of all-trans RA is not disease specific. Ketoconazole attenuates this accelerated catabolism, suggesting that oxidation by cytochrome-P450 enzymes is an important pathway for both constitutive and induced pathways of all-trans RA metabolism.
全反式维甲酸（all-trans RA）可使大多数急性早幼粒细胞白血病（APL）患者获得完全缓解。然而，持续口服给药会导致血浆药物浓度逐渐下降，这与复发及对这种维甲酸产生耐药性有关。我们推测，表明获得性耐药的药物水平下降部分是由可诱导的细胞色素P450氧化酶引起的，该酶可分解全反式维甲酸。
我们研究了全反式维甲酸在癌症患者中的临床药理学，以确定获得性耐药的可能机制，并评估细胞色素P450氧化酶抑制剂酮康唑逆转耐药的潜力。
54例APL或晚期肺癌患者单次口服全反式维甲酸（45mg/m²）后采集系列血浆样本。在34例晚期肺癌患者中，全反式维甲酸（45mg/m²）每日给药两次，共4周，在第2、28和29天，单次给予45mg/m²剂量后再次采集系列血浆样本。在第2和29天给药前1小时，单次口服一剂（200 - 1200mg）酮康唑。在这些患者的一个亚组以及11例早期肺癌患者中测定血浆中全反式维甲酸和13 - 顺式维甲酸的内源性浓度。
第1天全反式维甲酸的血浆药物浓度-时间曲线下平均面积（AUC）在患者之间差异很大。与APL患者相比，完成治疗的28例晚期肺癌患者在第1天的AUC水平显著更低（P = 0.06）；第1天水平低于300ng/mL·小时的一个亚组的血浆全反式维甲酸内源性浓度低于APL患者、早期肺癌患者或14名正常受试者。持续口服治疗后，全反式维甲酸第28天的平均AUC显著低于第1天（213ng/mL·小时对467ng/mL·小时；P < 0.01），酮康唑显著减弱了这种下降，酮康唑使第29天的血浆全反式维甲酸平均AUC增加至375ng/mL·小时（P < 0.01）。
报道的全反式维甲酸药代动力学变异性可能是由遗传或环境因素影响的基础分解代谢率的疾病相关或基于人群的差异所致。然而，全反式维甲酸的诱导分解代谢模式并非疾病特异性的。酮康唑减弱了这种加速的分解代谢，表明细胞色素P450酶的氧化是全反式维甲酸代谢的组成性和诱导性途径的重要途径。
