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Reduced Methadone Clearance During Aromatase Inhibition

Lu, Wenjie Jessie PhD*†; Thong, Nancy RN, CCRP*; Flockhart, David A. MD, PhD*†

Journal of Clinical Psychopharmacology: August 2012 - Volume 32 - Issue 4 - p 511–517
doi: 10.1097/JCP.0b013e31825d0b54
Original Contributions

Methadone is increasingly used in pain management and is a cornerstone in the treatment of opiate withdrawal. It is subject to highly variable clearance among patients. The complete metabolic disposition of methadone is likely to involve a number of enzymes, including specifically CYP2B6. Previous studies in vitro suggest that metabolism by aromatase may also contribute.

Single-dose methadone pharmacokinetics (2 mg, intravenous) were studied in 15 healthy postmenopausal women in the presence and absence of a potent aromatase inhibitor, letrozole. A sequential design was used, involving a control period followed by treatment with letrozole (2.5 mg/d, 11 days), in which each subject served as her own control.

On average, letrozole treatment reduced methadone systemic clearance by 22% (P = 0.001), increased methadone AUC by 23% (P = 0.007), and increased elimination half-life by 21% (P = 0.042). The plasma parent-to-metabolite ratio also increased (P = 0.009), and there was a linear relationship (R 2 = 0.74) between change in this plasma ratio and change in methadone AUC0–∞. In contrast, there was no such association with change in apparent urinary methadone clearance. Letrozole did not change methadone distribution half-life or its volume of distribution.

Overall, these data demonstrate a significant decrease in methadone clearance during coadministration of letrozole, consistent with decreased metabolism brought about by aromatase inhibition. An involvement of aromatase in the disposition of methadone may help explain the difficulty in methadone dosing and suggests a broader role for this catalyst of endogenous steroid metabolism in xenobiotic drug disposition.

From the *Division of Clinical Pharmacology, Indiana Institute for Personalized Medicine, and †Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN.

Received August 1, 2011; accepted after revision January 4, 2012.

Reprints: Wenjie Jessie Lu, PhD, 1001 West 10th St, Room 7123, Wishard Hospital, Myers Bldg, Indianapolis, IN 46202 (e-mail:

This study was funded in part by grants from the National Center for Research Resources (K24RR020815) to D.A.F., the National Institute for General Medical Sciences (T32GM008425) to D.A.F., and the Department of Defense Breast Cancer Research Program (W81XWH-11-1-0016) to W.J.L.

© 2012 Lippincott Williams & Wilkins, Inc.