Evan D. Kharasch, M.D., Ph.D.

Russell D. and Mary B. Shelden Professor
Anesthesiology
Division of Clinical & Translational Research
Director, Division of Clinical & Translational Research
Biochemistry and Molecular Biophysics

Biochemistry, Biophysics, and Structural Biology Program

  • 314-362-8796

  • 314-362-8025

  • 8054

  • 5510 CSRB

  • kharasch@wustl.edu

  • biomarkers, kidney, mass spectrometry, opiates, pain, translational research

  • Laboratory, translational and clinical investigations evaluate the role of drug metabolism and transport, and blood-brain and other tissue barriers, in drug disposition and clinical drug effects

Research Abstract:

The overall goal of my laboratory's research is to understand the mechanisms of interindividual variability in the therapeutic response to anesthetic and nonanesthetic drugs, with a focus on pharmacokinetics, pharmacodynamics and toxicity. These are directed towards optimizing drug disposition, drug safety, clinical efficacy, patient satisfaction, and pharmacoeconomics. Research encompasses both laboratory investigations of drug metabolism using human tissues and enzymes, and clinical volunteer and patient studies to confirm laboratory findings.

One major project addresses mechanisms of interindividual variability in opioid disposition and response, specifically with respect to hepatic and extra-hepatic metabolism, pharmacogenetic variation, stereochemistry, age and gender effects, drug interactions and dietary influences. In vitro models of opioid metabolism use human liver, intestinal and renal tissue to identify responsible P450s, and in vivo studies deliberately manipulate P450 activities and assess their pharmacokinetic and pharmacodynamic consequences. In addition, we are investigating the role of interstinal and blood brain barrier transport proteins in the oral absorption, bioavailability, and CNS access of various opioids. Specific studies are evaluating interactions between HIV drugs and long-acting opioids. The overall goal is to improve the use of opioids to treat cancer pain and drug abuse. Another major project addresses the development of novel noninvasive methods for assessing hepatic and intestinal cytochrome P450 activity in vivo. The goal is to detect interindividual variability in drug metabolizing activity, enzyme induction and inhibition caused by other drugs, and predict the disposition of drugs with narrow therapeutic indices in order to optimize therapy.

Another major project addresses the use of biomarkers in urine for the diagnosis of disease and drug toxicity. For example, we identified the first urine biomarker for noninvasive detection of renal cell and papillary kidney cancer.

Selected Publications:

Kharasch ED, Mitchell D, Coles R, Blanco R. Rapid clinical induction of hepatic cytochrome P4502B6 activity by ritonavir. Antimicrob Agents Chemother. 2008 52(5):1663-9.

Totah RA, Sheffels P, Roberts T, Whittington D, Thummel K, Kharasch ED. Role of CYP2B6 in stereoselective human methadone metabolism. Anesthesiology 2008 108:363-74.

Totah RA, Allen KE, Sheffels P, Whittington D, Kharasch ED. Enantiomeric metabolic interactions and stereoselective human methadone metabolism. J Pharmacol Exp Ther 2007 321:389-99.

Kharasch ED, Schroeder JL, Liggitt HD, Ensign D, Whittington D. New insights into the mechanism of methoxyflurane nephrotoxicity and implications for anesthetic development II. Identification of nephrotoxic metabolites. Anesthesiology 2006 105:737-745.

Lalovic B, Kharasch E, Hoffer C, Risler L, Liu-Chen L, and Shen D. Pharmacokinetics and pharmacodynamics of oral oxycodone in healthy human subjects: Role of circulating active metabolites. Clin Pharmacol Ther 2006 79:461-479.

Last Updated: 8/4/2011 10:13:21 AM

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