Evan D. Kharasch

The general theme of my research is anesthetic metabolism, and its relationship to anesthetic toxicity, pharmacokinetics, drug interactions, and safety.

Major areas of investigation include:
Volatile anesthetic and toxicity: in vitro models, molecular mechanisms, and clinical prevention. The objective is to identify biochemical mechanism of anesthetic hepatic and renal contributions to anesthetic metabolism, identify drug interactions and pathophysiology predisposing to anesthetic toxicity, and selectively manipulate P450 isozymes to prevent anesthetic toxicity in patients.

Mechanisms of interindividual differences in opioid anesthetic disposition. The objective is to identify the biochemical mechanisms responsible for interindividual variability in opioid pharmacokinetics. We aim to identify human P450 isozymes responsible for opioid metabolism, the population distribution, drug interactions, and pathophysiologic factors affecting P450 isoform expression and anesthetic disposition. We also aim toidentify the molecular mechanisms of age- and gender-related changes in opioiddisposition.

Stereochemistry and anesthetic disposition. Many anesthetics exist as racemates, or pairs of optically active enantiomers. These enantiomers may have significantly different anesthetic effects and rates of biotransformation. We aim to examine differences in human hepatic metabolism of volatile anesthetic stereoisomers, stereochemical differences in human ketamine metabolism and metabolic interactions between ketamine enantiomers; differences in pharmacokinetics, metabolism and toxicity of bupivacaine enantiomers; factors regulating the kinetics and toxicity of prolonged bupivacaine infusions used to treat cancer pain; and stereochemical differences in methadone pharmacokinetics and pharmacodynamics including pharmacokinetic-pharmacodynamic modeling.

Endogenous alkaloid opiates in humans. Evidence exists that mammals produce morphine and/or codeine as endogeneous opioids. Our objective is to characterize this system in humans. We aim to isolate and identify alkaloid opiates (morphine and codeine) as endogenous compounds in humans, the pathways and enzymes of endogenous alkaloid opiate synthesis in human tissues, and factors influencing tissue expression of endogenous alkaloid opiates.

Alcoholism, Drug Dependence and Clinical Pharmacology Study Section, Veterans Affairs Merit Research Review Board (1994-1996); Associate Editor, Survey of Anesthesiology (1994-present); Associate Editor, Anesthesiology (1995-present); American Society ofAnesthesiologists Research Committee(1998-present); Pharmacy and Therapeutics Committee, University of Washington Hospitals (1993-present), Seattle Veterans Affairs Medical Center (1988-present); University of Washington General Clinical Research Center Scientific Advisory Council (1997-present), Chair (1999-present); Director, Department of Anesthesiology Analytical and Core Laboratories (1992-present).