人肝细胞溶胶中纳曲酮形成6β-纳曲醇的动力学及抑制作用
Kinetics and inhibition of the formation of 6beta-naltrexol from naltrexone in human liver cytosol.
作者信息
Porter S J, Somogyi A A, White J M
机构信息
Department of Clinical and Experimental Pharmacology, University of Adelaide, Adelaide 5005, Australia.
出版信息
Br J Clin Pharmacol. 2000 Nov;50(5):465-71. doi: 10.1046/j.1365-2125.2000.00281.x.
AIMS
To determine the kinetics of the formation of 6beta-naltrexol from naltrexone in human liver cytosol, and to investigate the role of potential inhibitors.
METHODS
The kinetics of the formation of 6 beta-naltrexol from naltrexone were examined in eight human liver cytosol preparations using h.p.l.c. to quantify 6 beta-naltrexol and, the extent of inhibition of 6 beta-naltrexol formation was determined using chemical inhibitors. The formation of 6 beta-naltrexol and the back reaction of 6 beta-naltrexol to naltrexone were also examined in a microsomal preparation.
RESULTS
The Vmax, Km and CLint values for the formation of 6 beta-naltrexol from naltrexone were in the ranges of 16-45 nmol mg-1 protein h-1, 17-53 microM and 0.3-2.2 ml h-1 mg-1 protein, respectively. The steroid hormones testosterone (Ki = 0.3 +/- 0.1 microM) and dihydrotestosterone (Ki = 0.7 +/- 0.4 microM) were the most potent competitive inhibitors of 6 beta-naltrexol formation, with naloxone, menadione and corticosterone also producing > 50% inhibition at a concentration of 100 microM. The opioid agonists morphine, oxycodone, oxymorphone and hydromorphone, and a range of benzodiazepines showed < 20% inhibition at 100 microM. In the microsomal preparation, there was no formation of naltrexone from 6beta-naltrexol nor any formation of 6beta-naltrexol from naltrexone.
CONCLUSIONS
The intersubject variability in the kinetic parameters of 6beta-naltrexol formation could play a role in the efficacy of and patient compliance with naltrexone treatment. This variability could be due in part to a genetic polymorphism of the dihydrodiol dehydrogenase DD4, one of the enzymes reported to be responsible for the formation of 6beta-naltrexol from naltrexone. DD4 also has hydroxysteroid dehydrogenase activity which could account for the potent inhibition by the steroid hormones testosterone and dihydrotestosterone. The clinical significance of the latter finding remains to be established.
目的
确定纳曲酮在人肝细胞溶质中形成6β-纳曲醇的动力学，并研究潜在抑制剂的作用。
方法
使用高效液相色谱法（h.p.l.c.）在8份人肝细胞溶质制剂中检测纳曲酮形成6β-纳曲醇的动力学，以定量6β-纳曲醇，并使用化学抑制剂确定6β-纳曲醇形成的抑制程度。还在微粒体制剂中检测了6β-纳曲醇的形成以及6β-纳曲醇向纳曲酮的逆向反应。
结果
纳曲酮形成6β-纳曲醇的Vmax、Km和CLint值分别在16 - 45 nmol mg-1蛋白质 h-1、17 - 53 μM和0.3 - 2.2 ml h-1 mg-1蛋白质范围内。甾体激素睾酮（Ki = 0.3 ± 0.1 μM）和二氢睾酮（Ki = 0.7 ± 0.4 μM）是6β-纳曲醇形成的最有效竞争性抑制剂，纳洛酮、甲萘醌和皮质酮在100 μM浓度时也产生>50%的抑制作用。阿片类激动剂吗啡、羟考酮、羟吗啡酮和氢吗啡酮以及一系列苯二氮䓬类药物在100 μM时显示<20%的抑制作用。在微粒体制剂中，未观察到6β-纳曲醇形成纳曲酮，也未观察到纳曲酮形成6β-纳曲醇。
结论
6β-纳曲醇形成动力学参数的个体间差异可能在纳曲酮治疗的疗效和患者依从性中起作用。这种差异可能部分归因于二氢二醇脱氢酶DD4的基因多态性，DD4是据报道负责纳曲酮形成6β-纳曲醇的酶之一。DD4还具有羟类固醇脱氢酶活性，这可以解释甾体激素睾酮和二氢睾酮的强效抑制作用。后一发现的临床意义仍有待确定。
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