Methadone Pharmacokinetics Are Independent of Cytochrome P4503A (CYP3A) Activity and Gastrointestinal Drug Transport

Abstract

Background Methadone clearance is highly variable and drug interactions are problematic. Both have been attributed to CYP3A, but actual mechanisms are unknown. Drug interactions can provide such mechanistic information. Ritonavir/indinavir, one of the earliest protease inhibitor combinations, may inhibit CYP3A. We assessed ritonavir/indinavir effects on methadone pharmacokinetics and pharmacodynamics, intestinal and hepatic CYP3A activity, and intestinal transporters (P-glycoprotein) activity. CYP3A and transporters were assessed with alfentanil and fexofenadine, respectively. Methods Twelve healthy human immunodeficiency virus-negative volunteers underwent a sequential 3-part crossover. On three consecutive days they received oral alfentanil/fexofenadine, intravenous alfentanil, and intravenous plus oral (deuterium-labeled) methadone, repeated after acute (3d) and steady-state (2 wk) ritonavir/indinavir. Plasma and urine analytes were measured by mass spectrometry. Opioid effects were assessed by miosis. Results Alfentanil apparent oral clearance was inhibited >97% by both acute and steady-state ritonavir/indinavir, and systemic clearance was inhibited >90%, due to diminished hepatic and intestinal extraction. Ritonavir/indinavir increased fexofenadine area under the plasma concentration-time curve 4-to 5-fold, suggesting significant inhibition of gastrointestinal P-glycoprotein. Ritonavir/indinavir slightly increased methadone N-demethylation, but had no significant effects on methadone plasma concentrations, or on systemic or apparent oral clearance, renal clearance, hepatic extraction or clearance, or bioavailability. Ritonavir/indinavir had no significant effects on methadone plasma concentration-effect relationships. Conclusions Inhibition of both hepatic and intestinal CYP3A activity is responsible for ritonavir/indinavir 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. Methadone bioavailability was unchanged despite inhibition of gastrointestinal P-glycoprotein activity, suggesting that this transporter does not limit methadone intestinal absorption.

Oxycodone concentrations are greatly increased by the concomitant use of ritonavir or lopinavir/ritonavir

“…In HIV-negative subjects receiving buprenorphine/naloxone as opioid-replacement therapy, tipranavir/ritonavir reduced the formation of CYP3A4 dependent active metabolite norbuprenorphine, but the AUC of parent drug remained unchanged and no clinical opioid withdrawal symptoms were noted [47]. Contrary to the above mentioned studies, the concentrations of methadone have been decreased after ritonavir probably due to the induction of CYP2B6 [43]. Thus, the effect of ritonavir on important opioids can be opposite.…”

“…This could lead to bias, as the steady-state was not reached [21]. Ritonavir has been reported to cause an enzyme induction after approximately 2 weeks administration, which can diminish the inhibitory effects [42,43].…”

Methadone: A Substrate and Mechanism-Based Inhibitor of CYP19 (Aromatase)

“…The use of methadone is increasing, prescriptions having grown in the United States by 1300% between 1997 and 2006 (Kharasch et al, 2009), primarily as the result of its increasing use as a first-line analgesic. In addition, methadone maintenance therapy is the mainstay for the treatment of opioid addiction, but it is estimated that fewer than 10% of individuals who are addicted to heroin and prescription opioids are actually receiving methadone (Kleber, 2008).…”

“…The unpredictability of the effects of methadone due to these multiple characteristics results in a high incidence of inappropriate over-and underdosing. Inappropriate dosing can clearly cause severe adverse events such as withdrawal symptoms, respiratory depression, and electrocardiographic QT interval prolongation that can result in sudden cardiac death (Krantz et al, 2003;Kalgutkar et al, 2007;Sims et al, 2007;Kharasch et al, 2009).…”

“…Patients taking methadone often have coprescriptions for many other medica-tions and are therefore vulnerable to drug-drug interactions (Weschules et al, 2008). Poorly understood drug-drug interactions may thus contribute to the notable increase in methadone-related deaths (Sims et al, 2007) that has attended the increase in the use of the drug over the past decade (Kharasch et al, 2009). In addition, the effect of methadone itself on the metabolism or pharmacokinetics of other medications is understudied.…”