Loss-of-function polymorphisms in the organic cation transporter OCT1 are associated with reduced postoperative tramadol consumption
Loss-of-function polymorphisms in the organic cation transporter OCT1 are associated with reduced postoperative tramadol consumption
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DOI：
10.1097/j.pain.0000000000000662
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发表时间：
2016-11-01
期刊：
影响因子：
7.4
通讯作者：
Tzvetkov, Mladen V.
中科院分区：
文献类型：
--
作者：
Stamer, Ulrike M.;Frank, Musshoff;Tzvetkov, Mladen V.
有机阳离子转运蛋白OCT 1（SLC 22 A1）介导活性曲马多代谢产物（+）O-去甲基曲马多在肝脏中的摄取和代谢。在这项研究中，OCT 1基因多态性对术后恢复患者的药代动力学和曲马多镇痛疗效的影响进行了分析，除了CYP 2D 6基因型。入选通过患者自控镇痛接受曲马多的术后患者。确定导致0、1或2个活性OCT 1等位基因的基因型以及CYP 2D 6基因型。主要终点是0 vs至少1个活性OCT 1等位基因患者术后24小时的曲马多消耗量。次要终点是活性曲马多代谢产物（1）O-去甲基曲马多的OCT 1依赖性血浆浓度（浓度-时间曲线下面积）。在205例患者中，分别有19例、82例和104例携带0、1和2个活动OCT 1等位基因。与具有1或2个活性等位基因的患者组相比，具有0个活性OCT 1等位基因的患者通过患者自控镇痛的曲马多累积消耗量最低（343 +/- 235 vs 484 +/- 276 mg; P = 0.03）。多元回归分析显示，活跃OCT 1等位基因（P = 0.014）、CYP 2D 6（P = 0.001）、疼痛评分（P < 0.001）和手术范围（0.034）对曲马多用量有显著影响。在0、1或2个活性OCT 1等位基因携带者中，（1）O-去甲基曲马多的血药浓度-时间曲线下面积分别为111.8（95%置信区间：63.4-160.1）、80.2（65.1-95.3）和64.5（51.9-77.2）h.ng.mL（-1）（P = 0.03）。OCT 1功能丧失导致曲马多消耗量减少和（1）手术恢复患者中O-去甲基曲马多的血浆浓度增加。因此，在CYP 2D 6基因型旁边分析OCT 1可能会进一步改善未来的曲马多基因型依赖性剂量建议。
The organic cation transporter OCT1 (SLC22A1) mediates uptake and metabolism of the active tramadol metabolite (+)O-desmethyltramadol in the liver. In this study, the influence of OCT1 genetic polymorphisms on pharmacokinetics and analgesic efficacy of tramadol in patients recovering from surgery was analyzed in addition to the CYP2D6 genotype. Postoperative patients who received tramadol through patient-controlled analgesia were enrolled. Genotypes resulting in 0, 1, or 2 active OCT1 alleles were determined as well as CYP2D6 genotypes. The primary endpoint was the 24-hour postoperative tramadol consumption in patients with 0 vs at least 1 active OCT1 allele. Secondary endpoint was the OCT1-dependent plasma concentration (areas under the concentration-time curves) of the active tramadol metabolite (1) O-desmethyltramadol. Of 205 patients, 19, 82, and 104 carried 0, 1, and 2 active OCT1 alleles, respectively. Cumulative tramadol consumption through patient-controlled analgesia was lowest in patients with 0 active OCT1 allele compared with the group of patients with 1 or 2 active alleles (343 +/- 235 vs 484 +/- 276 mg; P = 0.03). Multiple regression revealed that the number of active OCT1 alleles (P = 0.014), CYP2D6 (P = 0.001), pain scores (P < 0.001), and the extent of surgery (0.034) had a significant influence on tramadol consumption. Plasma areas under the concentration-time curves of (1) O-desmethyltramadol were 111.8 (95% confidence interval: 63.4-160.1), 80.2 (65.1-95.3), and 64.5 (51.9-77.2) h.ng.mL(-1) in carriers of 0, 1, or 2 active OCT1 alleles (P = 0.03). Loss of OCT1 function resulted in reduced tramadol consumption and increased plasma concentrations of (1) O-desmethyltramadol in patients recovering from surgery. Therefore, analyzing OCT1 next to CYP2D6 genotype might further improve future genotype-dependent dose recommendations for tramadol.