Reduced methadone clearance during aromatase inhibition

Area of Science:

• Pharmacology
• Drug Metabolism

Background:

• Methadone is crucial for pain management and opioid withdrawal treatment.
• Patient variability in methadone clearance is a significant clinical challenge.
• CYP2B6 and potentially aromatase are implicated in methadone metabolism.

Purpose of the Study:

• To investigate the role of aromatase in methadone's metabolic disposition.
• To determine the effect of aromatase inhibition on methadone pharmacokinetics.

Main Methods:

• A sequential pharmacokinetic study in 15 healthy postmenopausal women.
• Administration of a single intravenous dose of methadone (2 mg).
• Treatment with letrozole (a potent aromatase inhibitor) for 11 days, with each subject serving as her own control.

Main Results:

• Letrozole reduced methadone systemic clearance by 22% (P=0.001).
• Methadone area under the curve (AUC) increased by 23% (P=0.007), and half-life increased by 21% (P=0.042).
• Increased plasma parent-to-metabolite ratio correlated with increased methadone AUC, indicating reduced metabolism.

Conclusions:

• Aromatase inhibition significantly decreases methadone clearance, suggesting aromatase involvement in its metabolism.
• This interaction may contribute to variability in methadone dosing.
• Aromatase may play a broader role in the disposition of xenobiotics.