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| |  P4503A Has No Effect on Clearing Methadone From the Body, Say Researchers ST. LOUIS, Mo -- March 3, 2009 -- Enzyme P4503A has no effect on clearing methadone from the body in patients taking protease inhibitors for HIV infection, according to a study published in the March issue of the journal Anesthesiology and online in the journal Drug and Alcohol Dependence. For years, enzyme P4503A was believed to be responsible for clearing methadone from the body. But when healthy volunteers were given a low dose of methadone together with protease inhibitors that caused profound decreases in the activity of P4503A, there was no reduction in the clearance of methadone. "Unfortunately, increased methadone use for pain has coincided with a significant increase in adverse events and fatalities related to methadone," said principal investigator Evan D. Kharasch, MD, Washington University School of Medicine, and Barnes-Jewish Hospital, St. Louis, Missouri. "The important message is that guidelines used by clinicians to direct methadone therapy may be incorrect." Dr. Kharasch and colleagues looked at interactions among methadone, the P4503A enzyme in the intestine and liver, and nelfinavir, indinavir, and ritonavir. They gave study volunteers a combination of ritonavir and indinavir. Both drugs profoundly inhibited the actions of the enzyme. If that enzyme were responsible for methadone clearance, then inhibiting it should have caused methadone to build up in the body. But the researchers found that it had no effect on methadone levels. Volunteers in the second study received nelfinavir. Again, the drug inhibited the action of the P4503A enzyme. That should have meant methadone concentrations would rise, but they actually decreased by half. "For more than a decade, practitioners have been warned about drug interactions involving the enzyme P4503A that might alter methadone metabolism," said Dr. Kharasch. "The package insert says inhibiting the enzyme may cause decreased clearance of methadone, but our research demonstrates that P4503A has no effect on clearing methadone from the body. So the package insert appears to be incorrect, or certainly needs to be re-evaluated, as do guidelines that explain methadone dosing and potential drug interactions." "The highest risk period for inadequate pain therapy or adverse side effects is during the first 2 weeks a patient takes methadone," said Dr. Kharasch. "If we can provide clinicians with better dosing guidelines, then I believe we will be able to better treat pain and limit deaths and other adverse events." "The research also is important for the treatment of HIV-AIDS," he continued. "Protease inhibitors can interfere with the activity of P4503A but increase the activity of P4502B. This paradox is highly unusual, and because these 2 enzymes metabolise so many prescription drugs, there are many potential drug interactions that we'll be able to understand better if we can get a better handle on how these pathways absorb drugs into the system and clear them from the body." SOURCE: Washington University in St. Louis - School of Medicine
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