Interactions Between Methadone and Antiretroviral Medications

John G. Gerber, MD
University of Colorado Health Sciences Center, Denver, Colorado

Methadone remains the drug most commonly used to treat narcotic addiction because it has withstood the test of time for safety and efficacy. Of its two isomers, R-methadone and S-methadone, only R-methadone is active. As a result, Dr. Gerber explained, methadone interaction studies must stereoselectively determine the effect of the interacting drug on these isomers.

Are In-vitro metabolism predictions reliable?

The metabolism of methadone was originally attributed primarily to the cytochrome P450 (CYP) 3A4 isoform. All protease inhibitors (PIs) inhibit CYP3A4 in the following order of potency:

Among the nonnucleoside reverse transcriptase inhibitors (NNRTIs), delavirdine inhibits CYP3A4 as well as CYP2C19. Efavirenz induces CYP3A4 and CYP2B6 while inhibiting CYP2C19. Nevirapine induces CYP3A4 and CYP2B6, and the antimycobacterial rifabutin induces CYP3A4.

On the basis of In-vitro estimates:

• Ritonavir should inhibit methadone metabolism, possibly causing toxicity.
• Rifabutin, efavirenz, and nevirapine should induce methadone metabolism.

But studies of people on methadone maintenance therapy contradicted some of these predictions. Although methadone maintenance patients in a rifabutin interaction study complained of opioid withdrawal symptoms, rifabutin actually had no effect on methadone concentrations [1]. Apparently study participants perceived withdrawal symptoms because they had been cautioned that they might experience withdrawal.

In AIDS Clinical Trials Group (ACTG) protocol 401, Dr. Gerber and colleagues measured 24-hour concentrations of methadone in 12 people before and 14 days after they began ritonavir/saquinavir at a dose of 400/400 mg twice daily [2]. The PIs lowered the area under the concentration-time curve (AUC) of both R- and S-methadone. But when results were corrected for plasma protein binding, the decrease in methadone exposure was much less. Concentrations of the inactive S-methadone decreased slightly more than concentrations of the active R-methadone, but these decreases were not large enough to cause opioid withdrawal symptoms. The ACTG 401 team concluded that methadone metabolism does not depend mainly on CYP3A4.

A study of methadone-nelfinavir interactions also found a decrease in concentrations of R-methadone and S-methadone [3]. Again, the decrease was greater for the inactive S-methadone, and study participants had no opioid withdrawal symptoms.

A study of 12 HIV-seronegative individuals on methadone maintenance compared the effects of indinavir for 8 days with the effects of placebo in a crossover design [4]. Indinavir did not affect methadone levels, while methadone decreased the maximum and increased the minimum concentrations of indinavir without any changes in AUC.

In methadone maintained patients amprenavir had little effect on concentrations of active R-methadone while significantly lowering exposure to inactive S-methadone [5]. Study participants experienced no withdrawal symptoms.

At steady state lopinavir/ritonavir decreased single dose methadone exposure, but this study did not measure levels of the R and S isomers [6]. Another study confirmed lower methadone concentrations with lopinavir/ritonavir but also failed to measure R-methadone and S-methadone [7]. Study participants were receiving methadone maintenance and had no narcotic withdrawal symptoms.

The CYP3A4 inducer efavirenz significantly lowered methadone concentrations in people on maintenance therapy and withdrawal symptoms were common [8]. In another study nevirapine had similar effects [9].

Making sense of the In-vivo data

On the basis of these findings, Dr. Gerber concluded that CYP3A4 could not be the major cytochrome P450 isoform involved in methadone metabolism. Neither rifabutin, a CYP3A4 inducer, nor indinavir, a CYP3A4 inhibitor, had an effect on methadone levels. In addition, ritonavir, the most potent CYP3A4 inhibitor, induced rather than inhibited methadone metabolism.

Although inducer PIs accelerated methadone metabolism and the NNRTIs efavirenz and nevirapine potently induced methadone metabolism, these drugs certainly induce CYPs other than CYP3A4. For example, both efavirenz and nevirapine potently induce CYP2B6.

Which CYP is mainly responsible for methadone metabolism? Using microsomes from a baculovirus-infected insect cell system expressing human specific human CYPs, Dr. Gerber screened all the drug-metabolizing enzymes. He found that only three isoenzymes metabolized methadone to EDDP to a great extent. He then performed full enzyme kinetics to calculate Vmax and Km in order to estimate which enzyme may be most important to methadone metabolism.

Dr. Gerber determined that CYP2B6 rapidly metabolizes methadone. CYP2C19 metabolizes methadone less than CYP2B6, and CYP3A4 less than CYP2C19. He concluded that CYP2B6 is the major isoform involved in methadone metabolism. Inactive S-methadone is metabolized faster with CYP2B6. With CYP2C19, active R-methadone is metabolized faster.

Dr. Gerber proposed the following conclusions:

1. Methadone is not mainly metabolized by CYP3A4 because:
   
   
   • Rifabutin has no effect on methadone pharmacokinetics;
   • Indinavir, a pure CYP3A4 inhibitor, has no effect on methadone pharmacokinetics;
   • Ritonavir induces rather than inhibits methadone metabolism.
   
   
2. Methadone is mainly metabolized by CYP2B6 because:
   
   
   • Methadone drug interactions are most prominent with CYP2B6 inducers (efavirenz, nevirapine, phenobarbital);
   • In-vitro, CYP2B6 has a higher Vmax and a lower Km than other CYP isoforms; methadone metabolism is stereoselective; and livers with higher CYP2B6 expression metabolize methadone more rapidly.
   
   
3. CYP2C19 could also play an important role in methadone metabolism.
   
   
4. PIs are safer than NNRTIs in methadone-using patients.

Dr. Gerber added that future drug-drug interaction studies must consider not only chiral metabolism issues, protein binding displacement, and pharmacodynamic correlates to pharmacokinetic alterations, but also the key CYPs that can effectively metabolize methadone at clinically relevant substrate concentrations.

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