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.