Kharasch Evan D, Hoffer Christine, Whittington Dale, Sheffels Pamela
Department of Anesthesiology, University of Washington, 1959 NE Pacific Street, RR-442, Seattle, WA 98195, USA.
Clin Pharmacol Ther. 2004 Sep;76(3):250-69. doi: 10.1016/j.clpt.2004.05.003.
The disposition of the long-acting opioid methadone, used to prevent opiate withdrawal and treat short- and long-lasting pain, is highly variable. Methadone undergoes N -demethylation to the primary metabolite 2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolinium (EDDP), catalyzed in vitro by intestinal, hepatic, and expressed cytochrome P450 (CYP) 3A4. However, the role of CYP3A4 in human methadone disposition in vivo is unclear. This investigation tested the hypothesis that CYP3A induction (or inhibition) would increase (or decrease) methadone metabolism and clearance in humans.
Healthy volunteers were studied in a randomized, balanced, 4-way crossover study. They received intravenous (IV) midazolam (to assess CYP3A4 activity) and then simultaneous oral deuterium-labeled and IV unlabeled methadone after pretreatment with rifampin (INN, rifampicin) (hepatic/intestinal CYP3A induction), troleandomycin (hepatic/intestinal CYP3A inhibition), grapefruit juice (selective intestinal CYP3A inhibition), or nothing. Methadone effects were measured by dark-adapted pupil diameter. CYP isoforms catalyzing methadone metabolism by human liver microsomes and expressed CYPs in vitro were also evaluated.
Methadone had high oral bioavailability (70%) and low intestinal (22%) and hepatic (9%) extraction, and there was a significant correlation ( r = 0.94, P <.001) between oral bioavailability and intestinal (but not hepatic) availability. Rifampin decreased bioavailability and oral and IV methadone plasma concentrations and increased IV clearance (4.42 +/- 1.00 mL. kg -1. min -1 versus 1.61 +/- 0.67 mL. kg -1. min -1, P <.05) and oral clearance (8.50 +/- 3.68 mL. kg -1. min -1 versus 2.05 +/- 0.92 mL. kg -1. min -1, P <.05), EDDP/methadone area under the curve (AUC) ratios, EDDP formation clearances, and hepatic extraction (0.27 +/- 0.06 versus 0.09 +/- 0.04, P <.05). Troleandomycin and grapefruit juice decreased the EDDP/methadone AUC ratio after oral methadone (0.17 +/- 0.10 and 0.14 +/- 0.06 versus 0.27 +/- 0.20, P <.05) but not IV methadone and had no effect on methadone plasma concentrations, IV clearance (1.29 +/- 0.41 mL. kg -1. min -1 and 1.48 +/- 0.55 mL. kg -1. min -1 ) or oral clearance (2.05 +/- 1.52 mL. kg -1. min -1 and 1.89 +/- 1.07 mL. kg -1. min -1 ), or other kinetic parameters. There was no correlation between methadone clearance and hepatic CYP3A4 activity. Pupil diameter changes reflected plasma methadone concentrations. In vitro experiments showed a predominant role for both CYP3A4 and CYP2B6 in liver microsomal methadone N -demethylation.
First-pass intestinal metabolism is a determinant of methadone bioavailability. Intestinal and hepatic CYP3A activity only slightly affects human methadone N -demethylation but has no significant effect on methadone concentrations, clearance, or clinical effects. Greater rifampin effects, compared with troleandomycin and grapefruit juice, on methadone disposition suggest a major role for intestinal transporters and for other CYPs, such as CYP2B6. Interindividual variability and drug interactions affecting intestinal transporter and hepatic CYP3A and CYP2B6 activity may alter methadone disposition.
用于预防阿片类药物戒断及治疗短期和长期疼痛的长效阿片类药物美沙酮的处置情况高度可变。美沙酮经N -去甲基化生成主要代谢产物2-乙基-1,5-二甲基-3,3-二苯基吡咯鎓（EDDP），在体外由肠道、肝脏及表达的细胞色素P450（CYP）3A4催化。然而，CYP3A4在人体内美沙酮处置中的作用尚不清楚。本研究检验了以下假设：CYP3A诱导（或抑制）会增加（或降低）人体中美沙酮的代谢及清除率。
在一项随机、平衡、四交叉研究中对健康志愿者进行研究。他们先静脉注射（IV）咪达唑仑（以评估CYP3A4活性），然后在接受利福平（国际非专利药品名称，利福平）（肝脏/肠道CYP3A诱导）、醋竹桃霉素（肝脏/肠道CYP3A抑制）、葡萄柚汁（选择性肠道CYP3A抑制）预处理或不做预处理后，同时口服氘标记的美沙酮和静脉注射未标记的美沙酮。通过暗适应瞳孔直径测量美沙酮的作用。还评估了催化人肝微粒体中美沙酮代谢的CYP同工酶及体外表达的CYPs。
美沙酮具有高口服生物利用度（70%）及低肠道（22%）和肝脏（9%）提取率，口服生物利用度与肠道（而非肝脏）利用率之间存在显著相关性（r = 0.94，P <.001）。利福平降低了生物利用度、口服及静脉注射美沙酮的血浆浓度，并增加了静脉清除率（4.42±1.00 mL·kg -1·min -1对1.61±0.67 mL·kg -1·min -1，P <.05）和口服清除率（8.50±3.68 mL·kg -1·min -1对2.05±0.92 mL·kg -1·min -1，P <.05）、EDDP/美沙酮曲线下面积（AUC）比值、EDDP形成清除率及肝脏提取率（0.27±0.06对0.09±0.04，P <.05）。醋竹桃霉素和葡萄柚汁降低了口服美沙酮后的EDDP/美沙酮AUC比值（0.17±0.10和0.14±0.06对0.27±0.20，P <.05），但对静脉注射美沙酮无此影响，且对美沙酮血浆浓度、静脉清除率（1.29±0.41 mL·kg -1·min -1和1.48±0.55 mL·kg -1·min -1）或口服清除率（2.05±1.52 mL·kg -1·min -1和1.89±1.07 mL·kg -1·min -1）或其他动力学参数无影响。美沙酮清除率与肝脏CYP3A4活性之间无相关性。瞳孔直径变化反映了血浆美沙酮浓度。体外实验表明CYP3A4和CYP2B6在肝微粒体美沙酮N -去甲基化中均起主要作用。
首过肠道代谢是美沙酮生物利用度的一个决定因素。肠道和肝脏CYP3A活性仅轻微影响人体中美沙酮的N -去甲基化，但对美沙酮浓度、清除率或临床效果无显著影响。与醋竹桃霉素和葡萄柚汁相比，利福平对美沙酮处置的影响更大，这表明肠道转运体及其他CYPs（如CYP2B6）起主要作用。个体间差异以及影响肠道转运体和肝脏CYP3A及CYP2B6活性的药物相互作用可能会改变美沙酮的处置情况。
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