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.

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 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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA025931-05
Application #
8286380
Study Section
Special Emphasis Panel (ZDA1-GXM-A (07))
Program Officer
Khalsa, Jagjitsingh H
Project Start
2008-09-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$328,423
Indirect Cost
$112,355
Name
Washington University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Lenze, Eric J; Farber, Nuri B; Kharasch, Evan et al. (2016) Ninety-six hour ketamine infusion with co-administered clonidine for treatment-resistant depression: A pilot randomised controlled trial. World J Biol Psychiatry 17:230-8
Kharasch, Evan D; Eisenach, James C (2016) Wherefore Gabapentinoids?: Was There Rush Too Soon to Judgment? Anesthesiology 124:10-2
Kharasch, Evan D; Brunt, L Michael (2016) Perioperative Opioids and Public Health. Anesthesiology 124:960-5
Kharasch, Evan D (2015) Opioid Half-lives and Hemlines: The Long and Short of Fashion. Anesthesiology 122:969-70
Campbell, Scott D; Gadel, Sarah; Friedel, Christina et al. (2015) Influence of HIV antiretrovirals on methadone N-demethylation and transport. Biochem Pharmacol 95:115-25
Brier, Matthew R; Wu, Qian; Tanenbaum, Aaron B et al. (2015) Effect of HAART on Brain Organization and Function in HIV-Negative Subjects. J Neuroimmune Pharmacol 10:517-21
Kharasch, Evan D; Hollmann, Markus W (2015) Steroid Anesthesia Revisited: Again. Anesth Analg 120:983-4
Kharasch, Evan D; Regina, Karen J; Blood, Jane et al. (2015) Methadone Pharmacogenetics: CYP2B6 Polymorphisms Determine Plasma Concentrations, Clearance, and Metabolism. Anesthesiology 123:1142-53
Meissner, Konrad; Blood, Jane; Francis, Amber M et al. (2014) Cyclosporine-inhibitable cerebral drug transport does not influence clinical methadone pharmacodynamics. Anesthesiology 121:1281-91
Sai, Kiran Kumar Solingapuram; Fan, Jinda; Tu, Zhude et al. (2014) Automated radiochemical synthesis and biodistribution of [¹¹C]l-α-acetylmethadol ([¹¹C]LAAM). Appl Radiat Isot 91:135-40

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