The overall goal of this research is to improve treatment of the intertwined diseases of opiate addiction, HIV/AIDS and coexisting opportunistic infections. Methadone and buprenorphine are the cornerstone therapies for opiate addiction, however their disposition is characterized by unexplained variability. Moreover, highly active antiretroviral therapy (HAART) for HIV/AIDS causes clinically significant, complex, and insufficiently understood drug interactions with both methadone and buprenorphine, which may cause opiate withdrawal, toxicity, and treatment failures. The antitubercular drug rifampin interacts with methadone, but whether this occurs with buprenorphine, and the underlying mechanism(s) for either, are unknown. Better in vitro and clinical models for assessing human drug interactions are needed. While pharmacologic activity in animals is recognized for some buprenorphine metabolites,their biological activity in humans is unknown. HAART drug interactions with addiction therapies are both pharmacokinetic and pharmacodynamic, but incompletely understood. Predictable therapeutic guidelines remain elusive. This research will evaluate the hypotheses that buprenorphine metabolites may be pharmacologically active in humans, that methadone, buprenorphine, and buprenorphine metabolites may be substrates for hepatic, intestinal, and/or blood brain transport proteins, and that HAART and antitubercular drugs interact with these transporters to alter buprenorphine and methadone pharmacokinetics, pharmacodynamic, and clinical effects.
The aims of this research program are to define the human pharmacology of buprenorphine metabolites, identify the human membrane transporters for which methadone, buprenorphine, and metabolites are substrates, and assess the influence of HAART and rifampin on these pathways, and their role in clinical drug interactions. A concerted laboratory, translational and clinical approach to these aims will be pursued. Transporter-transfected cells, tissue-derived cells, and novel co-culture cell models will be used to identify transporters relevant to buprenorphine and methadone, the effects of HAART and anti-TB drugs. Novel in vivo probes will be used in mechanistically-driven and therapeutically applicable clinical protocols to identify drug interactions and their mechanism(s). Clinical studies will use methods for determining opioid brain penetration and pharmacodynamics. Successful completion of the aims will provide fundamental new information on buprenorphine disposition, improve therapeutic guidance and safety, and enhance the treatments and outcomes of opiate addiction and HIV/AIDS. Public Health Relevance: The proposed research is relevant to improving the clinical treatment of the significant public health problems of HIV/AIDS, substance abuse,drug interactions,and the rising incidence of serious adverse complications from drug interactions. It is also relevant to creating a better basic understanding of how drugs enter the brain and are inactivated by the body, and how therapeutic drugs affect healthy and ill individuals.
The proposed research is relevant to improving the clinical treatment of the significant public health problems of HIV/AIDS, substance abuse,drug interactions,and the rising incidence ofserious adverse complications from drug interactions. It is also relevant to creating a better basic understanding of how drugs enter the brain and are inactivated by the body, and how therapeutic drugs affect healthy and ill individuals.
|Sai, Kiran Kumar Solingapuram; Fan, Jinda; Tu, Zhude et al. (2014) Automated radiochemical synthesis and biodistribution of [¹¹C]l-?-acetylmethadol ([¹¹C]LAAM). Appl Radiat Isot 91:135-40|
|Campbell, Scott D; Regina, Karen J; Kharasch, Evan D (2014) Significance of lipid composition in a blood-brain barrier-mimetic PAMPA assay. J Biomol Screen 19:437-44|
|Crews, K R; Gaedigk, A; Dunnenberger, H M et al. (2014) Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450 2D6 genotype and codeine therapy: 2014 update. Clin Pharmacol Ther 95:376-82|
|Kaspera, Rüdiger; Kirby, Brian J; Sahele, Tariku et al. (2014) Investigating the contribution of CYP2J2 to ritonavir metabolism in vitro and in vivo. Biochem Pharmacol 91:109-18|
|Kharasch, Evan D; Coopersmith, Craig M (2013) Sleeping to survive?: The impact of volatile anesthetics on mortality in sepsis. Anesthesiology 119:755-6|
|Kharasch, Evan D; Rosow, Carl E (2013) Assessing the utility of the utility function. Anesthesiology 119:504-6|
|Regina, Karen J; Kharasch, Evan D (2013) High-sensitivity analysis of buprenorphine, norbuprenorphine, buprenorphine glucuronide, and norbuprenorphine glucuronide in plasma and urine by liquid chromatography-mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 939:23-31|
|Kharasch, Evan D (2012) Getting oil and water to mix. Anesthesiology 116:504-6|
|Fan, Jinda; Brown, Sarah M; Tu, Zhude et al. (2011) Chemical and enzyme-assisted syntheses of norbuprenorphine-3-?-D-glucuronide. Bioconjug Chem 22:752-8|
|Kharasch, Evan D (2011) Intraoperative methadone: rediscovery, reappraisal, and reinvigoration? Anesth Analg 112:13-6|