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

The Russell D. and Mary B. Shelden Professor of Anesthesiology and Chief, Clinical Research Division in the Department of Anesthesiology

B.S. in Medical Science (1977)
Northwestern University

Medical Degree (1979)
Northwestern University Medical School
(6 year combined B.S.-M.D. program)

Ph.D. in Pharmacology (1983)
Northwestern University

Internship (1985)
University of Washington Hospitals
Seattle, Washington

Residency/Anesthesiology Research Fellowship (1988)
University of Washington Hospitals
Seattle, Washington

The overall goal of my laboratory's research is to optimize drug disposition, clinical efficacy, drug safety, and patient satisfaction. A major focus is the basic and clinical pharmacology of analgesics and analgesia, seeking to understand the role of disposition and metabolism in patient response and toxicity. The research is translational, and encompasses laboratory investigations of drug metabolism using human tissues and enzymes, and clinical volunteer and patient studies to confirm and validate laboratory findings. The paradigm is bedside to bench and back.
One major project addresses the mechanism of interindividual variability in opioid disposition and response, specifically with respect to 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 cytochrome 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, and interactions between herbal medications and opioids. The overall goal is to improve the use of opioids to treat acute pain, cancer pain and drug abuse.
A second major project addresses development of novel noninvasive methods for assessing hepatic and intestinal cytochrome P450 activity in humans 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.
A third major project addresses the pharmacology of COX-2 inhibitors as preemptive and therapeutic measures for perioperative pain, and the potential role of prostanoid-mediated central sensitization in postoperative pain. We are investigating the CNS disposition of COX-2 inhibitors, the perioperative formation of peripheral and central cytokines and prostanoids, and their modulation by COX-2 inhibitors.
A fourth major area of interest is alternative routes of drug administration for control of chronic and breakthrough cancer pain. Specifically, we have evaluated nasal opioid administration as an alternative for oral and parenteral administration, specifically targeting the treatment of breakthrough cancer pain.

2007

Coles R, and Kharasch ED. Stereoselective analysis of bupropion and hydroxybupropion in human plasma and urine by LC/MS/MS. J Chromatogr B Analyt Technol Biomed Life Sci . 2007 Sep 15;857(1):67-75. Epub 2007 Jul 10.

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Kharasch ED, Walker A, Isoherranen N, Hoffer C, Sheffels P, thummel K, whittington D, and Ensign D. Influence of CYP3A5 Genotype on the Pharmacokinetics and Pharmacodynamics of the Cytochrome P4503A Probes Alfentanil and Midazolam. Clin Pharmacol Ther. 2007 Oct;82(4):410-26. Epub 2007 Jun 6.

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Feierman DE, Trunfio G, Morankar A, and Kharasch ED. More than polymorphism. Anesth Analg . 2007 Jun;104(6):1605; author reply 1605-6.

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Templeton IE, Thummel KE, Kharasch ED, Kunze KL, Hoffer C, Nelson WL, and Isoherranen N. Contribution of Itraconazole Metabolites to Inhibition of CYP3A4 In Vivo. Clin Pharmacol Ther. 2007 May 9 epub ahead of print.

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Kharasch ED. Every breath you take, we'll be watching you. Anesthesiology. 2007 Apr;106(4):652-4.

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Totah RA, Allen KE, Sheffels P, Whittington D, and Kharasch ED. Enantiomeric metabolic interactions and stereoselective human methadone metabolism. J Pharmacol Exp Ther. 2007 Apr;321(1):389-99. Epub 2007 Jan 26.

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2006

Bruce RD, McCance-Katz E, Kharasch ED, Moody DE, and Morse GD. Pharmacokinetic interactions between buprenorphine and antiretroviral medications. Clin Infect Dis 43 Suppl 4: S216-23. 2006

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Kirby B, Kharasch ED, Thummel KT, Narang VS, Hoffer CJ, and Unadkat JD. Simultaneous measurement of in vivo P-glycoprotein and cytochrome P450 activities. J Clin Pharmacol. 46(11): 1313-9. 2006

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Kharasch ED, Schroeder JF, Liggitt HD, Ensign D, and Whittington D. New insights into the mechanism of methoxyflurane nephrotocicity and implications for anesthetic development (part 1): Identification of the nephrotoxic metabolic pathway. Anesthesiology 105(4): 737-45. 2006.

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Kharasch ED, Schroeder JF, Liggitt HD, Ensign D, and Whittington D. New insights into the mechanism of methoxyflurane nephrotocicity and implications for anesthetic development (part 2): Identification of nephrotoxic metabolites. Anesthesiology 105(4): 737-45. 2006

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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, 79(5): 461-79, 2006.

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Jackson DL, Milgrom P, Heacox GA, and Kharasch ED.  Pharmacokinetics and clinical effects of multidose sublingual triazolam in healthy volunteers. J Clin Psychopharmacol, 26(1): 4-8, 2006.

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Kunze KL, Nelson WL, Sharasch ED, Thummel KE, and Isoherranen N.  Stereochemical aspects of itraconazole metabolism in vitro and in vivo. Drug Metab Dispos. 34(4): 583-90, 2006.

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2005

Chaobal H, Kharasch ED: Single-point sampling for assessment of constitutive, induced, and inhibited cytochrome P450 3A activity with alfentanil or midazolam. Clin Pharmacol Ther, 78:529-39, 2005.

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Kharasch ED, Walker A, Hoffer C, Sheffels P: Sensitivity of intravenous and oral alfentanil and pupillary miosis as noninvasive probes for hepatic and first-pass CYP3A activity. J Clin Pharmacol, 45:1187-1197, 2005.

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Kharasch ED, Whittington D, Hoffer C, Krudys K, Craig K, Vicini P, Sheffels P, Lalovic B: The paradoxical role of hepatic and intestinal cytochrome P4503A (CYP3A) in the bioactivation and clinical effects of l-a-acetylmethadol (LAAM). Clin Pharmacokinet. 44:731-751, 2005.

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Klees TM, Sheffels P, Dale O, Kharasch ED: Metabolism of alfentanil by cytochrome P4503A (CYP3A) isoforms. Drug Metab Dispos, 33:303-311, 2005.

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Klees TM, Sheffels P, Thummel KE, Kharasch ED: Pharmacogenetic determinants of human liver microsomal alfentanil metabolism and the role of cytochrome P4503A5 (CYP3A5). Anesthesiology, 102:550-556, 2005

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Dembo G, Park S, Kharasch ED: Central nervous system concentrations of cyclooxygenase-2 inhibitors in humans. Anesthesiology, 102:409-415, 2005.

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Kharasch ED, Walker A, Hoffer C, Sheffels P: Evaluation of first-pass cytochrome P4503A (CYP3A) and P-glycoprotein activities using alfentanil and fexofenadine in combination. J Clin Pharmacol, 45:79-88, 2005.

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2004

Kharasch ED, Walker A, Hoffer C, Sheffels P: Intravenous and oral alfentanil as in vivo probes for hepatic and first-pass CYP3A activity. Noninvasive assessment using pupillary miosis. Clin Pharmacol Ther, 76:452-66, 2004.

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Kharasch ED, Hoffer C, Whittington D, Sheffels P: Role of hepatic and intestinal cytochrome CYP3A and CYP2B6 in the metabolism, disposition and miotic effects of methadone. Clin Pharmacol. Ther, 76:250-269, 2004.

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Kharasch ED, Hoffer C, Whittington D: Influence of age on the pharmacokinetics and pharmacodynamics of oral transmucosal fentanyl citrate. Anesthesiology, 101:738-43, 2004.

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Kharasch ED, Whittington D, Hoffer C: Influence of hepatic and intestinal cytochrome P4503A (CYP3A) activity on the acute disposition and effects of oral transmucosal fentanyl citrate (OTFC). Anesthesiology, 101:729-37, 2004.

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Dale O, Sheffels P, Kharasch ED: Bioavailablilities of rectal and oral methadone in healthy subjects. Br J Clin Pharmacol, 58:156-162, 2004.

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Kharasch ED, Hoffer C, Altuntas G, Whittington D: Quinidine as a probe for the role of P-glycoprotein in the intestinal absorption and clinical effects of fentanyl. J Clin Pharmacol, 44:224-33, 2004.

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Kharasch ED, Hoffer C, Whittington D: The effect of quinidine, used as a probe for the involvement of P-glycoprotein, on the intestinal absorption and pharmacodynamics of methadone. Br J Clin Pharmacol, 57: 600-610, 2004.

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2003

Kharasch ED, Hoffer C, Whittington D, Sheffels P: Role of P-glycoprotein in the intestinal absorption and clinical effects of morphine. Clin Pharmacol. Ther. 74:543-554, 2003.

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Fitzgibbon D, Morgan D, Dockter D, Barry C, Kharasch ED: Initial pharmacokinetic, safety and efficacy evaluation of nasal morphine gluconate for breakthrough pain in cancer patients. Pain 106:309-315, 2003.

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2002

Dale O, Hoffer C, Sheffels P, Kharasch ED: Disposition of nasal, intravenous and oral methadone in healthy volunteers. Clin Pharmacol Ther 72:536-545, 2002.

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Dale O, Hjortkjær R, Kharasch ED: Nasal administration of opioids for pain management in adults. Acta Anaesth Scand 46:759-770, 2002.

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2001

Oda Y, Kharasch ED: Metabolism of methadone and Levo-a-acetylmethadol (LAAM) by human intestinal P4503A4 (CYP3A4): Potential contribution of intestinal metabolism to pre-systemic clearance and bioactivation. J Pharmacol Exp Ther 298:1021-1032, 2001.

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Oda Y, Kharasch ED: Metabolism of Levo- -acetylmethadol (LAAM) by human liver cytochrome P450: Involvement of CYP3A4 characterized by atypical kinetics with two binding sites. J Pharmacol Exp Ther 297:410-422, 2001.

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