Role of cytochrome P4502B6 in methadone metabolism and clearance.
Role of cytochrome P4502B6 in methadone metabolism and clearance.
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DOI：
10.1002/jcph.1
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发表时间：
2013-03
影响因子：
2.9
通讯作者：
Stubbert, Kristi
中科院分区：
文献类型：
--
作者：
Kharasch, Evan D.;Stubbert, Kristi
美沙酮N-去甲基化在体外由肝细胞色素P4502 B6（CYP 2B 6）和CYP 3A 4催化，但临床处置通常归因于CYP 3A 4。本研究使用基于体内机制的CYP 2B 6抑制剂噻氯匹定口服给药4天，验证了CYP 2B 6是一种主要的美沙酮N-去甲基化和清除的CYP 2B 6亚型的假设。使用CYP 3A 4/5底物探针阿芬太尼的初步临床研究确定噻氯匹定不会抑制肠或肝CYP 3A 4/5。受试者在噻氯匹定前后接受静脉内+口服（氘标记）外消旋美沙酮。噻氯匹定显著且立体选择性地（S>R）抑制美沙酮N-去甲基化，降低血浆代谢物/美沙酮曲线下面积比和代谢物形成清除率。在静脉和口服给药后，噻氯匹定还使R-和S-美沙酮的剂量调整血浆曲线下面积分别显著增加20%和60%。CYP 2B 6抑制可降低美沙酮N-去甲基化和清除率，并改变美沙酮浓度，证明CYP 2B 6在美沙酮临床处置中的主要作用。
Methadone N-demethylation in vitro is catalyzed by hepatic cytochrome P4502B6 (CYP2B6) and CYP3A4, but clinical disposition is often attributed to CYP3A4. This investigation tested the hypothesis that CYP2B6 is a prominent CYP isoform responsible for clinical methadone N-demethylation and clearance, using the in vivo mechanism-based CYP2B6 inhibitor ticlopidine, given orally for 4 days. A preliminary clinical investigation with the CYP3A4/5 substrate probe alfentanil established that ticlopidine did not inhibit intestinal or hepatic CYP3A4/5. Subjects received intravenous plus oral (deuterium-labeled) racemic methadone before and after ticlopidine. Ticlopidine significantly and stereoselectively (S>R) inhibited methadone N-demethylation, decreasing plasma metabolite/methadone area under the curve ratios and metabolite formation clearances. Ticlopidine also significantly increased the dose-adjusted plasma area under the curve for R- and S-methadone by 20% and 60%, respectively, after both intravenous and oral dosing. CYP2B6 inhibition reduces methadone N-demethylation and clearance, and alters methadone concentrations, demonstrating a predominant role for CYP2B6 in clinical methadone disposition.
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影响因子：
3.7
作者：
Fonseca F;de la Torre R;Díaz L;Pastor A;Cuyàs E;Pizarro N;Khymenets O;Farré M;Torrens M
通讯作者：
Torrens M
影响因子：
6.7
作者：
通讯作者：
--
影响因子：
3.8
作者：
Friedland, G;Andrews, L;O'Mara, E
通讯作者：
O'Mara, E
影响因子：
3.9
作者：
Lu, Wenjie Jessie;Bies, Robert;Flockhart, David A.
通讯作者：
Flockhart, David A.
DOI：
10.1016/j.jpain.2008.10.008
发表时间：
2009-02
期刊：
The journal of pain
影响因子：
--
作者：
Chou R;Fanciullo GJ;Fine PG;Adler JA;Ballantyne JC;Davies P;Donovan MI;Fishbain DA;Foley KM;Fudin J;Gilson AM;Kelter A;Mauskop A;O'Connor PG;Passik SD;Pasternak GW;Portenoy RK;Rich BA;Roberts RG;Todd KH;Miaskowski C;American Pain Society-American Academy of Pain Medicine Opioids Guidelines Panel
通讯作者：
American Pain Society-American Academy of Pain Medicine Opioids Guidelines Panel