Opioids in Cancer Pain & Drug Abuse: Optimizing Therapy
Principal Investigator: Evan Kharasch
Affiliation: Washington University School of Medicine
Abstract: The overall objective of this renewal application is to sustain and expand the PI's patient-oriented research program in the pharmacology of opioids and HIV/AIDS drugs, specifically directed towards the therapy of substance abuse and pain. A principal component of this program will be the development of beginning clinical investigators. The specific research objectives are to 1) continue existing research which investigates mechanisms of variability in human opioid disposition, pharmacodynamics and clinical efficacy, and endeavors to optimize opioid therapy of substance abuse and cancer pain, 2) expand existing research on the mechanism of drug interactions with HIV/AIDS drugs and their clinical consequence, 3) facilitate program expansion into underutilized therapies such as nonsteroidal antiinflammatory drugs, and 4) mentor beginning clinical investigators in patient-oriented research, utilizing the above framework to spawn independent research programs. A critical focus will be interfacing in vitro and in vivo aspects of human drug disposition and efficacy, and translating recent discoveries in basic enzymology and pharmacogenetics of drug disposition into clinical strategies for optimized therapy. Methadone maintenance is the cornerstone of opiate abuse therapy, a vital and effective strategy for HTV/AIDS risk reduction, and widely used for cancer pain treatment. Methadone is characterized by extreme, unexplained, and unpredictable interindividual pharmacokinetic variability, causing inadequate pain treatment, opioid abstinence syndrome, treatment failures, and unwanted side effects. Methadone is metabolized by hepatic and intestinal cytochrome P450, and is a substrate for transporters in the intestine, brain, and kidney. Mechanism(s) of individual variability in methadone metabolism and transport are, however, unknown, as are their clinical consequences. Highly active antiretroviral therapy (HAART) is the cornerstone HIV/AIDS treatment, yet HIV/AIDS drugs cause profound, complex, and poorly understood drug interactions. To address these questions, experiments in vitro will use human liver and intestinal microsomes and transfected cell lines to identify relevant P450 isoforms and transporters and probe drug-drug interactions. Complementary clinical investigations will verify these identifications and establish the mechanism of HTV/AIDS drug interactions, and the influence of drug interactions and pharmacogenetics on opioid disposition and pharmacologic effects. Successful identification of the factors affecting metabolism, clearance, and clinical effects of methadone will improve the clinical outcome and reduce the costs of opiate addiction and cancer pain treatment. Successful identification of the mechanism of HIV/AIDS drug interactions will improve the therapy of HIV/AIDS.
Funding Period: 1999-05-01 - 2010-03-31
more information: NIH RePORT
- Metabolism of alfentanil by cytochrome p4503a (cyp3a) enzymesTheresa Mariero Klees
Department of Anesthesiology, Box 356540, University of Washington, 1959 NE Pacific, RR-442, Seattle, WA 98195, USA
Drug Metab Dispos 33:303-11. 2005..Alfentanil is one of the few CYP3A substrates that is metabolized in vitro as avidly by both CYP3A4 and 3A5. Polymorphic CYP3A5 expression may contribute to inter-individual variability in alfentanil metabolism...
- Stereoselective analysis of bupropion and hydroxybupropion in human plasma and urine by LC/MS/MSRebecka Coles
Division of Clinical and Translational Research, Department of Anesthesiology, Washington University, St Louis, MO 63110, USA
J Chromatogr B Analyt Technol Biomed Life Sci 857:67-75. 2007..The predominant enantiomers in both urine and plasma were (R)-bupropion and (R,R)-hydroxybupropion. This is the first LC-MS/MS assay to analyze the enantiomers of both bupropion and hydroxybupropion in plasma and urine...
- Stereoselective metabolism of bupropion by cytochrome P4502B6 (CYP2B6) and human liver microsomesRebecka Coles
Division of Clinical and Translational Research, Department of Anesthesiology, Washington University, St Louis, Missouri 63110 1093, USA
Pharm Res 25:1405-11. 2008..Bupropion is chiral, used clinically as a racemate, and disposition is stereoselective. Nevertheless, it is unknown whether CYP2B6-catalyzed bupropion hydroxylation is stereoselective...
- Rapid clinical induction of hepatic cytochrome P4502B6 activity by ritonavirEvan D Kharasch
Division of Clinical and Translational Research, Department of Anesthesiology, Washington University, 660 S Euclid Ave, Campus Box 8054, St Louis, MO 63110 1093, USA
Antimicrob Agents Chemother 52:1663-9. 2008..The ritonavir induction of CYP2B6 activity may have significant implications for drug interactions and clarify previously unexplained interactions...
- Stereoselective bupropion hydroxylation as an in vivo phenotypic probe for cytochrome P4502B6 (CYP2B6) activityEvan D Kharasch
Division of Clinical and Translational Research, Department of Anesthesiology, Washington University, St Louis, MO 63110 1093, USA
J Clin Pharmacol 48:464-74. 2008....
- Role of CYP2B6 in stereoselective human methadone metabolismRheem A Totah
Department of Medicinal Chemistry, Washington University in St Louis, USA
Anesthesiology 108:363-74. 2008..Expressed CYP2B6 and also CYP2C19 N-demethylate methadone in vitro. This investigation tested the hypothesis that CYPs 2B6, 3A4, and/or 2C19 are responsible for stereoselective methadone metabolism in human liver microsomes and in vivo...
- Molecular characterization of CYP2B6 substratesSean Ekins
Collaborations in Chemistry, 601 Runnymede Ave, Jenkintown, PA 19046 USA
Curr Drug Metab 9:363-73. 2008..We have shown that CYP2B6 substrates are generally small hydrophobic molecules that are frequently central nervous system active, which may be important for drug discovery research...
- Methadone pharmacokinetics are independent of cytochrome P4503A (CYP3A) activity and gastrointestinal drug transport: insights from methadone interactions with ritonavir/indinavirEvan D Kharasch
Division of Clinical and Translational Research, Department of Anesthesiology, Washington University in St Louis, St Louis, Missouri 63110 1093, USA
Anesthesiology 110:660-72. 2009..CYP3A and transporters were assessed with alfentanil and fexofenadine, respectively...
- Methadone metabolism and clearance are induced by nelfinavir despite inhibition of cytochrome P4503A (CYP3A) activityEvan D Kharasch
Department of Anesthesiology, and Department of Biochemistry and Molecular Biophysics, Washington University in St Louis, St Louis, MO 63110, USA
Drug Alcohol Depend 101:158-68. 2009..CYP3A4/5 and transporters were assessed using alfentanil and fexofenadine, respectively...
- Mechanism of ritonavir changes in methadone pharmacokinetics and pharmacodynamics: II. Ritonavir effects on CYP3A and P-glycoprotein activitiesE D Kharasch
Division of Clinical and Translational Research, Department of Anesthesiology, Washington University, St Louis, Missouri, USA
Clin Pharmacol Ther 84:506-12. 2008..Ritonavir inhibited both intestinal and hepatic CYP3A and drug transport. ALF miosis noninvasively determined CYP3A inhibition by ritonavir...
- The metabotropic glutamate receptor subtype 5 antagonist fenobam is analgesic and has improved in vivo selectivity compared with the prototypical antagonist 2-methyl-6-(phenylethynyl)-pyridineMichael C Montana
Washington University Pain Center, Department of Anesthesiology, 660 S Euclid Ave, St Louis, MO 63110, USA
J Pharmacol Exp Ther 330:834-43. 2009..These results demonstrate that fenobam is analgesic in mice and has an improved in vivo selectivity for mGlu5 over MPEP...
- Influence of CYP3A5 genotype on the pharmacokinetics and pharmacodynamics of the cytochrome P4503A probes alfentanil and midazolamE D Kharasch
Division of Clinical and Translational Research, Department of Anesthesiology, Washington University, St Louis, Missouri, USA
Clin Pharmacol Ther 82:410-26. 2007....
- Contribution of itraconazole metabolites to inhibition of CYP3A4 in vivoI E Templeton
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington, USA
Clin Pharmacol Ther 83:77-85. 2008..Accounting for circulating metabolites of ITZ significantly improved the in vitro to in vivo extrapolation of CYP3A4 inhibition compared to a consideration of ITZ exposure alone...
- Evaluation of first-pass cytochrome P4503A (CYP3A) and P-glycoprotein activities using alfentanil and fexofenadine in combinationEvan D Kharasch
Department of Anesthesiology, Box 356540, University of Washington, 1959 NE Pacific Street RR-442, Seattle, WA 98195, USA
J Clin Pharmacol 45:79-88. 2005..Alfentanil and fexofenadine in combination appear to be a useful probe for evaluating both first-pass CYP3A and P-gp activities in humans...
- Central nervous system concentrations of cyclooxygenase-2 inhibitors in humansGregory Dembo
Department of Anesthesiology, University of Washington, Seattle, USA
Anesthesiology 102:409-15. 2005..This supports the hypothesis that coxibs may act, in part, in the human CNS, provide important new information on the mechanism and treatment of pain and may guide coxib selection for therapeutic trials when CNS penetration is desirable...
- Pharmacogenetic determinants of human liver microsomal alfentanil metabolism and the role of cytochrome P450 3A5Theresa Mariero Klees
Norwegian University of Science and Technology, Trondheim, Norway
Anesthesiology 102:550-6. 2005..Further investigation is warranted to assess whether the CYP3A5 polymorphism is a factor in the interindividual variability of alfentanil metabolism and clearance in vivo...
- Paradoxical role of cytochrome P450 3A in the bioactivation and clinical effects of levo-alpha-acetylmethadol: importance of clinical investigations to validate in vitro drug metabolism studiesEvan D Kharasch
Department of Anesthesiology, University of Washington, Seattle, Washington 98195, USA
Clin Pharmacokinet 44:731-51. 2005..It also related changes in LAAM disposition during enzyme inhibition or induction to any changes in pharmacological effect...
- Single-point sampling for assessment of constitutive, induced, and inhibited cytochrome P450 3A activity with alfentanil or midazolamHarshvardhan N Chaobal
Departments of Anesthesiology and Medicinal Chemistry, University of Washington, 660 South Euclid Avenue, St. Louis, MO 63110-1093, USA
Clin Pharmacol Ther 78:529-39. 2005....
- Stereochemical aspects of itraconazole metabolism in vitro and in vivoKent L Kunze
Department of Pharmaceutics, H272 Health Sciences Building, Box 357610, University of Washington, Seattle, WA 98195, USA
Drug Metab Dispos 34:583-90. 2006..However, stereoselective elimination was diminished after multiple dosing, presumably as a result of CYP3A4 autoinhibition. In conclusion, the metabolism of ITZ is highly stereoselective in vitro and in vivo...
- Pharmacokinetics and pharmacodynamics of oral oxycodone in healthy human subjects: role of circulating active metabolitesBojan Lalovic
Department of Pharmaceutics, University of Washington, Seattle 98195, USA
Clin Pharmacol Ther 79:461-79. 2006..The central opioid effects of oxycodone are governed by the parent drug, with a negligible contribution from its circulating oxidative and reductive metabolites...
- Simultaneous measurement of in vivo P-glycoprotein and cytochrome P450 3A activitiesBrian Kirby
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, WA 98195 7610, USA
J Clin Pharmacol 46:1313-9. 2006..Coadministration of digoxin and midazolam can be used to simultaneously phenotype P-gp and CYP3A activity without a significant pharmacokinetic interaction...
- Pharmacokinetic interactions between buprenorphine and antiretroviral medicationsR Douglas Bruce
Yale University AIDS Program, New Haven, CT 06511, USA
Clin Infect Dis 43:S216-23. 2006..Review of the current state of knowledge regarding specific interactions between buprenorphine and antiretrovirals is followed by a review of the clinical applicability of these interactions...
- Enantiomeric metabolic interactions and stereoselective human methadone metabolismRheem A Totah
Department of Medicinal Chemistry, University of Washington Seattle, Washington, USA
J Pharmacol Exp Ther 321:389-99. 2007..In vivo, CYP2B6 may be a major determinant of methadone metabolism and disposition, and CYP2B6 activity and stereoselective metabolic interactions may confer variability in methadone disposition...