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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DA013209-03
Application #
6523192
Study Section
Special Emphasis Panel (ZRG1-BDCN-6 (01))
Program Officer
Khalsa, Jagjitsingh H
Project Start
2000-09-30
Project End
2004-08-31
Budget Start
2002-09-01
Budget End
2004-08-31
Support Year
3
Fiscal Year
2002
Total Cost
$167,000
Indirect Cost
Name
Tufts University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02111
Perloff, Michael D; von Moltke, Lisa L; Fahey, Jeanne M et al. (2007) Induction of P-glycoprotein expression and activity by ritonavir in bovine brain microvessel endothelial cells. J Pharm Pharmacol 59:947-53
Greenblatt, David J; Harmatz, Jerold S; Karim, Aziz (2007) Age and gender effects on the pharmacokinetics and pharmacodynamics of ramelteon, a hypnotic agent acting via melatonin receptors MT1 and MT2. J Clin Pharmacol 47:485-96
Greenblatt, David J; von Moltke, Lisa L; Luo, Yan et al. (2006) Ginkgo biloba does not alter clearance of flurbiprofen, a cytochrome P450-2C9 substrate. J Clin Pharmacol 46:214-21
Girard, Hugo; Villeneuve, Lyne; Court, Michael H et al. (2006) The novel UGT1A9 intronic I399 polymorphism appears as a predictor of 7-ethyl-10-hydroxycamptothecin glucuronidation levels in the liver. Drug Metab Dispos 34:1220-8
Culm-Merdek, Kerry E; von Moltke, Lisa L; Gan, Lu et al. (2006) Effect of extended exposure to grapefruit juice on cytochrome P450 3A activity in humans: comparison with ritonavir. Clin Pharmacol Ther 79:243-54
He, Ping; Court, Michael H; Greenblatt, David J et al. (2006) Factors influencing midazolam hydroxylation activity in human liver microsomes. Drug Metab Dispos 34:1198-207
Hesse, Leah M; Greenblatt, David J; von Moltke, Lisa L et al. (2006) Ritonavir has minimal impact on the pharmacokinetic disposition of a single dose of bupropion administered to human volunteers. J Clin Pharmacol 46:567-76
Greenblatt, David J; Leigh-Pemberton, Richard A; von Moltke, Lisa L (2006) In vitro interactions of water-soluble garlic components with human cytochromes p450. J Nutr 136:806S-809S
Fahey, Jeanne M; Grassi, Jeffrey M; Reddi, Jyoti M et al. (2006) Acute zolpidem administration produces pharmacodynamic and receptor occupancy changes at similar doses. Pharmacol Biochem Behav 83:21-7
Bertelsen, Kirk M; Greenblatt, David J; von Moltke, Lisa L (2006) Apparent active transport of MDMA is not mediated by P-glycoprotein: a comparison with MDCK and Caco-2 monolayers. Biopharm Drug Dispos 27:219-27

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