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Journal of Medical Case Reports

, 5:513

First Online: 10 October 2011Received: 28 April 2011Accepted: 10 October 2011DOI: 10.1186-1752-1947-5-513

Cite this article as: Lu, W.J., Zhou, W., Kreutz, Y. et al. J Med Case Reports 2011 5: 513. doi:10.1186-1752-1947-5-513

Abstract

IntroductionThe use of methadone as an analgesic is on the increase, but it is widely recognized that the goal of predictable and reproducible dosing is confounded by considerable variability in methadone pharmacokinetics, and unpredictable side effects that include sedation, respiratory depression and cardiac arrhythmias. The mechanisms underlying these unpredictable effects are frequently unclear. Here, to the best of our knowledge we present the first report of an association between accidental methadone overexposure and increased plasma protein binding, a new potential mechanism for drug interactions with methadone.

Case presentationWe describe here the cases of two patients who experienced markedly different responses to the same dose of methadone during co-administration of letrozole. Both patients were post-menopausal Caucasian women who were among healthy volunteers participating in a clinical trial. Under the trial protocol both patients received 6 mg of intravenous methadone before and then after taking letrozole for seven days. One woman aged 59 experienced symptoms consistent with opiate overexposure after the second dose of methadone that were reversed by naloxone, while the other aged 49 did not. To understand the etiology of this event, we measured methadone pharmacokinetics in both patients. In our affected patient only, a fourfold to eightfold increase in methadone plasma concentrations after letrozole treatment was observed. Detailed pharmacokinetic analysis indicated no change in metabolism or renal elimination in our patient, but the percentage of unbound methadone in the plasma decreased 3.7-fold. As a result, the volume of distribution of methadone decreased approximately fourfold. The increased plasma binding in our affected patient was consistent with observed increases in plasma protein concentrations.

ConclusionsThe marked increase in the total plasma methadone concentration observed in our patient, and the enhanced pharmacodynamic effect, appear primarily due to a reduced volume of distribution. The extent of plasma methadone binding may help to explain the unpredictability of its pharmacokinetics. Changes in volume of distribution due to plasma binding may represent important causes of clinically meaningful drug interactions.

Electronic supplementary materialThe online version of this article doi:10.1186-1752-1947-5-513 contains supplementary material, which is available to authorized users.

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Author: Wenjie J Lu - Weidong Zhou - Yvonne Kreutz - David A Flockhart

Source: https://link.springer.com/







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