Substance abuse among patients with human immunodeficiency virus (HIV) infection is a matter of major public health concern. Some 25-30 percent of HIV-infected patients have acquired the disease through IV. drug-use; a principal therapeutic objective is to sustain abstinence, both for patients' health and to minimize risk of disease dissemination, through maintenance programs using methadone or buprenorphine. For these and other HIV-infected patients, the emotional burden of the disease produces comorbidity with depression, anxiety, and sleep disorders. Benzodiazepine agonists are commonly prescribe for anxiety and insomnia, and there is concern regarding abuse of this class of drugs. Highly active antiretroviral therapies (HAART), including the HIV protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs), constitute major advances in the treatment of HIV infecffon, but greatly complicate the link between HIV/AID' and substance abuse. HIV PIs and NNRTls may inhibit and/or induce the activity of human Cytochrome P4503A (CYP3A) enzymes, responsible for the metabolism of buprenorphine, methadone, many benzodiazepines and for the formation of the hepatotoxic metabolite of cocaine. CYP3A inhibition could promote methadone toxicity, or enhance abusability of benzodiazopines; CYP3A induction could precipitate methadone withdrawal and opiate relapse, or enhance cocaine hepatotoxicity. The applicants propose to apply in vitromodels, using human liver microsomal preparations, to determine the capacity of HIV PIs (ritonavir, nelfinavir, indinavir, saquinavir) and of NNRTls tdelavirdine, nevirapine, efavirenz) to inhibit CYP3A-mediated metabolism of methadone, buprenorphine, triazolam, alprazolam, flunitrazepam, and cocaine. In vitro in vivoscaling paradigms will be used to estimate the probability of clinically important in vivointeractions. The validity of the model will be prospectively tested in controlled clinical pharmacokinetic-pharmacodynamic studies of triazolam coadministered with ritonavir or delavirdine, and of methadone coadministered with thes' same two HMRT drugs. The time-course and extent of CYP3A induction by ritonavir, and the net balance of inhibition and induction, are tested in a controlled study of triazolam kinetics and dynamics before, during, and after extended exposure to ritonavir. The in vitro model, if validated, has the potential to provide clinically important information on interactions involving HIV treatments and abusable drugs, at relatively low cost and with no human drug exposure.
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