Paroxetine increases steady-state concentrations of (R)-methadone in CYP2D6 extensive but not poor metabolizers
Paroxetine increases steady-state concentrations of (R)-methadone in CYP2D6 extensive but not poor metabolizers
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DOI：
10.1097/00004714-200204000-00017
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发表时间：
2002-04-01
影响因子：
2.9
通讯作者：
Eap, CB
中科院分区：
文献类型：
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作者：
Begré, S;von Bardeleben, U;Eap, CB
在10例接受美沙酮维持治疗的成瘾患者中，在平均12天的时间内，在引入帕罗西汀20 mg/天前后，测量了(R)美沙酮（即活性形式）、(S)-美沙酮和（R，S）-美沙酮的稳态血药浓度。8例患者基因分型为CYP2D6纯合子广泛代谢者（EMs）， 2例为差代谢者（pm）。帕罗西汀显著增加了全组美沙酮两种对映体的浓度((R)-美沙酮+/- SD平均增加26 +/- 32%；范围：-14%至+83%，p = 0.032；(S)-美沙酮为49 +/- 51%；范围：-29%至+137%，p = 0.028；（R，S）美沙酮为35±41%；(R)-美沙酮、(S)-美沙酮和（R，S）-美沙酮的平均增加32%，p = 0.036; （53%,p = 0.028; 42%,p = 0.036）。另一方面，在两个pm中，帕罗西汀增加了(S)-美沙酮浓度，但没有增加(R)美沙酮浓度（平均分别增加36%和3%）。帕罗西汀是一种强CYP2D6抑制剂，这些结果证实了先前的研究表明CYP2D6参与美沙酮代谢，对(R)对映体具有立体选择性。由于帕罗西汀是CYP1A2、CYP2C9、CYP2C19和CYP3A4的轻度抑制剂，EMs和pm中(S)-美沙酮浓度的增加可以通过抑制这些同工酶中的任何一种来介导。
Steady-state blood concentrations of (R)methadone (i.e., the active form), (S)-methadone, and (R,S)-methadone were measured before and after introduction of paroxetine 20 mg/day during a mean period of 12 days in 10 addict patients in methadone maintenance treatment. Eight patients were genotyped as CYP2D6 homozygous extensive metabolizers (EMs) and two patients as poor metabolizers (PMs). Paroxetine significantly increased concentrations of both enantiomers of methadone in the whole group (mean increase for (R)-methadone +/- SD, 26 +/- 32%; range, -14% to +83%, p = 0.032; for (S)-methadone, 49 +/- 51%; range, -29% to +137%, p = 0.028; for (R,S)methadone, 35 +/- 41%; range, -20% to + 112%, p = 0.032) and in the group of eight EMs (mean increase, 32%,p = 0.036; 53%,p = 0.028; and 42%,p = 0.036, for (R)-methadone, (S)-methadone, and (R,S)-methadone, respectively). On the other hand, in the two PMs, (S)-methadone but not (R)methadone concentrations were increased by paroxetine (mean increases of 36% and 3% respectively). Paroxetine is a strong CYP2D6 inhibitor, and these results confirm previous studies showing an involvement of CYP2D6 in methadone metabolism with a stereoselectivity toward the (R)enantiomer. Because paroxetine is a mild inhibitor of CYP1A2, CYP2C9, CYP2C19, and CYP3A4, increase of (S)-methadone concentrations in both EMs and PMs could be mediated by inhibition of any of these isozymes.