The influence of CYP2D6 polymorphism and quinidine on the disposition and antitussive effect of dextromethorphan in humans
The influence of CYP2D6 polymorphism and quinidine on the disposition and antitussive effect of dextromethorphan in humans
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DOI：
10.1016/s0009-9236(96)90056-9
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发表时间：
1996-09-01
影响因子：
6.7
通讯作者：
Somogyi, AA
中科院分区：
文献类型：
--
作者：
Capon, DA;Bochner, F;Somogyi, AA
目的：我们研究了快代谢型和慢代谢型受试者中美沙芬的分布，以及这种多态性对美沙芬镇咳作用的影响。方法：在四种情况下研究了六种快代谢型受试者：（1）30 mg美沙芬后，（2）30 mg美沙芬后，50 mg奎尼丁前1小时，（3）安慰剂后，（4）50 mg奎尼丁后。在两种情况下研究了6种弱代谢者：（1）30 mg美沙芬后和（2）安慰剂后，在168小时内收集血液和尿液，并测定美沙芬、总（结合和未结合）右啡烷、3-甲氧基吗啡喃和总3-羟基吗啡喃。在每个场合，在每个血液采样时间，辣椒素作为气雾剂给药，以挑起cooke.Results：右美沙芬的血浆浓度-时间曲线（AUC）下的面积是150倍以上的慢代谢者比在快代谢者，奎尼丁增加了AUC在快代谢者43倍。中位右美沙芬半衰期在弱代谢者中为19.1小时，在给予奎尼丁的快代谢者中为5.6小时，在快代谢者中为2.4小时。对于右美沙芬（作为总数），AUC在弱代谢者中降低8.6倍;奎尼丁对AUC没有影响。中位半衰期在弱代谢者中为10.1小时，在快代谢者中为6.6小时，在快代谢者中为1.4小时。在弱代谢者中，右美沙芬至右啡烷的表观部分清除率为1.2 L/hr，在给予奎尼丁的快代谢者中为78.5 L/hr，在快代谢者中为970 L/hr。在研究前尿代谢率和右美沙芬对右美沙芬的部分清除率之间存在强（r（2）= 0.82）和显著（p < 0.01）正相关。对辣椒素的反应性存在很大的受试者间差异。三组中辣椒素诱导的咳嗽频率无差异。右美沙芬在本实验性咳嗽模型中无镇咳作用。结论：CYP 2D 6状态对右美沙芬的处置有显著影响。辣椒素可能不是实验性咳嗽研究的理想药物。
Objectives: We studied the disposition of dextromethorphan in extensive and poor metabolizer subjects, as well as the effect of this polymorphism on the antitussive action of dextromethorphan,Methods: Six extensive metabolizers were studied on four occasions: (1) after 30 mg dextromethorphan, (2) after 30 mg dextromethorphan 1 hour before 50 mg quinidine, (3) after placebo, and (4) after 50 mg quinidine. Six poor metabolizers were studied on two occasions: (1) after 30 mg dextromethorphan and (2) after placebo, Blood and urine were collected over 168 hours and assayed for dextromethorphan, total (conjugated and unconjugated) dextrorphan, 3-methoxymorphinan, and total 3-hydroxymorphinan. On each occasion at each blood sampling time, capsaicin was administered as an aerosol to provoke cough.Results: Dextromethorphan area under the plasma concentration-time curve (AUC) was 150-fold greater in the poor metabolizers than in the extensive metabolizers, and quinidine increased the AUC in extensive metabolizers 43-fold. The median dextromethorphan half-life was 19.1 hours in poor metabolizers, 5.6 hours in extensive metabolizers given quinidine, and 2.4 hours in extensive metabolizers, For dextrorphan (as total), the AUC was reduced 8.6-fold in poor metabolizers; quinidine had no effect on the AUC. The median half-life was 10.1 hours in poor metabolizers, 6.6 hours in extensive metabolizers given quinidine, and 1.4 hours in extensive metabolizers. The apparent partial clearance of dextromethorphan to dextrorphan was 1.2 L/hr in poor metabolizers, 78.5 L/hr in extensive metabolizers given quinidine, and 970 L/hr in extensive metabolizers. There was a strong (r(2) = 0.82) and significant (p < 0.01) positive correlation between the prestudy urinary metabolic ratios and the partial clearances of dextromethorphan to dextrorphan. There was very large intersubject variability in responsiveness to capsaicin. There was no difference in the capsaicin-induced cough frequency in the three groups. Dextromethorphan had no antitussive effect in this experimental cough model,Conclusion: The disposition of dextromethorphan was substantially influenced by CYP2D6 status. Capsaicin may not be an ideal agent in experimental cough studies.