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Methadone Appears Not to Interact with HIV Protease Inhibitors

HIV protease inhibitors (PIs) are processed by the cytochrome P450 (CYP450) system in the liver and can interfere with the activity of specific CYP450 enzymes. This can lead to slower processing -- and thus higher levels -- of other drugs metabolized by the same enzymes.

Many drugs are processed by the CYP3A enzyme and therefore interact with PIs, especially ritonavir (Norvir). Since the PIs were first introduced, experts believed that one such drug was methadone, a synthetic opiate used for pain management and maintenance therapy for people addicted to heroin. Clinicians and patients were warned that using PIs and methadone together might result in high levels of methadone, possibly leading to overdose.

But new research, published in the March 2009 issue of Anesthesiology, indicates that CYP3A does not play a role in methadone metabolism, and therefore methadone is unlikely to interact with PIs.

Evan Kharasch from Washington University School of Medicine in St. Louis and colleagues analyzed the effects of ritonavir-boosted indinavir (Crixivan) and nelfinavir (Viracept) on methadone pharmacokinetics and pharmacodynamics, intestinal and hepatic (liver) CYP3A activity, and intestinal transporter (P-glycoprotein) activity in 12 healthy, HIV negative volunteers.

CYP3A and intestinal transporters were assessed using alfentanil (Alfenta, a short-acting opiate used for pain relief) and fexofenadine (the allergy medication Allegra and generic equivalents), respectively.

In this sequential 3-part crossover study, participants received oral alfentanil/fexofenadine, intravenous alfentanil, and intravenous plus oral (deuterium-labeled) methadone on 3 consecutive days, repeated after acute (3 days) and steady-state (2 weeks) administration of indinavir/ritonavir. The researchers also conducted a second study using nelfinavir.

Results

• Apparent oral clearance of alfentanil was inhibited more than 97% by both acute and steady-state indinavir/ritonavir.
• Systemic clearance of alfentanil was inhibited more than 90% due to diminished hepatic and intestinal extraction of the drug.
• Indinavir/ritonavir increased fexofenadine concentrations over time (area under the curve) by 4- to 5-fold, suggesting significant inhibition of gastrointestinal P-glycoprotein.
• Indinavir/ritonavir slightly increased methadone N-demethylation.
• However, it had no significant effects on methadone plasma concentrations or on systemic or apparent oral clearance, renal (kidney) clearance, hepatic extraction or clearance, or bioavailability.
• Indinavir/ritonavir had no significant effects on methadone plasma concentration-effect relationships.
• Nelfinavir also did not increase methadone levels (in fact, methadone decreased when the drugs were administered together).

Based on these findings, the study authors concluded, "Inhibition of both hepatic and intestinal CYP3A activity is responsible for [indinavir/ritonavir] drug interactions."

"Methadone disposition was unchanged, despite profound inhibition of CYP3A activity, suggesting little or no role for CYP3A in clinical methadone metabolism and clearance," they added. "Methadone bioavailability was unchanged, despite inhibition of gastrointestinal P-glycoprotein activity, suggesting that this transporter does not limit methadone intestinal absorption."

These results help explain the various studies over the past decade that have shown no clinically relevant interactions between PIs and methadone.

Kharasch said the findings were important because the interaction warnings in PI package inserts may lead clinicians to prescribe inappropriate doses of methadone, which can result in inadequate pain relief or withdrawal symptoms if too low, and suppressed respiration and even death if too high.

The researchers are now attempting to determine whether another CYP450 enzyme besides CYP3A -- including, possibly, CYP2B -- is responsible for methadone metabolism.

3/20/09

Reference

ED Kharasch, C Hoffer, D Whittington, and others. Methadone pharmacokinetics are independent of cytochrome P4503A (CYP3A) activity and gastrointestinal drug transport: insights from methadone interactions with ritonavir/indinavir. Anesthesiology 110(3): 660-672. March 2009. (Abstract).