Inhibition of CYP2D6-mediated tramadol O-demethylation in methadone but not buprenorphine maintenance patients
Inhibition of CYP2D6-mediated tramadol O-demethylation in methadone but not buprenorphine maintenance patients
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DOI：
10.1111/j.1365-2125.2012.04256.x
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发表时间：
2012-11-01
影响因子：
3.4
通讯作者：
Somogyi, Andrew A.
中科院分区：
文献类型：
--
作者：
Coller, Janet K.;Michalakas, Jennifer R.;Somogyi, Andrew A.
由于阿片类药物的交叉耐受性等诸多问题，阿片类药物依赖个体的疼痛管理存在问题。因此，有必要找到替代阿片类药物的镇痛药，曲马多可能是这样的替代品之一。美沙酮在体内外均抑制CYP2D6。我们的目的是研究美沙酮对曲马多代谢途径的影响：在维持美沙酮或丁丙诺啡作为对照的受试者中，o -去甲基化（CYP2D6）到阿片活性代谢物M1和n -去甲基化（CYP3A4）到M2。与服用丁丙诺啡的受试者相比，美沙酮降低了曲马多对活性o -去甲基曲马多（M1）的清除率，但对n -去甲基曲马多（M2）的形成没有影响。与可待因等其他由CYP2D6形成活性代谢物的镇痛药类似，o -去甲基曲马多（M1）形成减少可能导致维持美沙酮的受试者镇痛减少。因此，应该在这一患者群体中使用代谢不依赖于CYP2D6的替代镇痛药。目的比较O- （CYP2D6介导）和N- （CYP3A4介导）曲马多去甲基化代谢在美沙酮和丁丙诺啡维持CYP2D6广泛代谢的受试者之间的差异。方法9例美沙酮维持组和7例丁丙诺啡维持组给予盐酸曲马多100 mg单剂量。4小时采血，检测曲马多、美沙酮、丁丙诺啡和去甲丁丙诺啡（如适用），4小时以上所有尿液检测曲马多及其M1和M2代谢物。结果美沙酮组o -去甲基化（M1）尿代谢率[中位数（范围）][0.071(0.0120.103)]显著低于丁丙诺啡组[0.192 (0.1080.392)](P= 0.0002，概率评分1.0)，而n -去甲基化（M2）尿代谢率[中位数（范围）]差异无统计学意义（P= 0.21，概率评分0.69）。与丁丙诺啡相比，美沙酮组M1的剂量[中位（范围）]回收率显著低于丁丙诺啡组（分别为0.069（0.0440.093）和0.126 (0.0690.187)，P= 0.04，概率评分0.19）；美沙酮组M2显著高于丁丙诺啡组（分别为0.048（0.0330.085）和0.033 (0.0140.049)，P= 0.04，概率评分0.81）。曲马多相似（分别为0.901（0.6351.30）和0.685 (0.3471.04)，P= 0.35，概率得分0.65）。结论美沙酮抑制cyp2d6介导的曲马多对M1的代谢。因此，由于阿片类镇痛的程度很大程度上取决于M1的形成，美沙酮维持患者可能无法通过口服曲马多获得足够的镇痛。
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Management of pain in opioid dependent individuals is problematic due to numerous issues including cross-tolerance to opioids. Hence there is a need to find alternative analgesics to classical opioids and tramadol is potentially one such alternative. Methadone inhibits CYP2D6 in vivo and in vitro. We aimed to investigate the effect of methadone on the pathways of tramadol metabolism: O-demethylation (CYP2D6) to the opioid-active metabolite M1 and N-demethylation (CYP3A4) to M2 in subjects maintained on methadone or buprenorphine as a control. WHAT THIS STUDY ADDS Compared with subjects on buprenorphine, methadone reduced the clearance of tramadol to active O-desmethyl-tramadol (M1) but had no effect on N-desmethyltramadol (M2) formation. Similar to other analgesics whose active metabolites are formed by CYP2D6 such as codeine, reduced formation of O-desmethyltramadol (M1) is likely to result in reduced analgesia for subjects maintained on methadone. Hence alternative analgesics whose metabolism is independent of CYP2D6 should be utilized in this patient population. AIMS To compare the O- (CYP2D6 mediated) and N- (CYP3A4 mediated) demethylation metabolism of tramadol between methadone and buprenorphine maintained CYP2D6 extensive metabolizer subjects. METHODS Nine methadone and seven buprenorphine maintained subjects received a single 100 mg dose of tramadol hydrochloride. Blood was collected at 4 h and assayed for tramadol, methadone, buprenorphine and norbuprenorphine (where appropriate) and all urine over 4 h was assayed for tramadol and its M1 and M2 metabolites. RESULTS The urinary metabolic ratio [median (range)] for O-demethylation (M1) was significantly lower (P= 0.0002, probability score 1.0) in the subjects taking methadone [0.071 (0.0120.103)] compared with those taking buprenorphine [0.192 (0.1080.392)], but there was no significant difference (P= 0.21, probability score 0.69) in N-demethylation (M2). The percentage of dose [median (range)] recovered as M1 was significantly lower in subjects taking methadone compared with buprenorphine (0.069 (0.0440.093) and 0.126 (0.0690.187), respectively, P= 0.04, probability score 0.19), M2 was significantly higher in subjects taking methadone compared with buprenorphine (0.048 (0.0330.085) and 0.033 (0.0140.049), respectively, P= 0.04, probability score 0.81). Tramadol was similar (0.901 (0.6351.30) and 0.685 (0.3471.04), respectively, P= 0.35, probability score 0.65). CONCLUSIONS Methadone inhibited the CYP2D6-mediated metabolism of tramadol to M1. Hence, as the degree of opioid analgesia is largely dependent on M1 formation, methadone maintenance patients may not receive adequate analgesia from oral tramadol.