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University of Maryland Baltimore
Experimental Therapeutics Symposium 2009

Published in: Education, Health & Medicine
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  1. 1. Enhancing the bioactivation of Cyclophosphamide by hepatic Drug-metabolizing Enzymes Hongbing Wang Department of Pharmaceutical Sciences
  2. 2. Cyclophosphamide CYCLOPHOSPHAMIDE Breast cancer Ovarian cancer Leukemia Lymphomas Prostate cancer Lung cancer Multiple myeloma Systemic lupus erythematosus Rheumatoid arthritis ……
  3. 3. Metabolism of Cyclophosphamide
  4. 4. Cytochrome P450s Wang H , et al. Current Drug Metabolism 2008
  5. 5. Transcriptional regulation of CYP2B and CYP3A Wang H. et. al CDM 2003
  6. 6. hCAR selectively induces CYP2B6 over CYP3A4 RIF = Selective hPXR Activator CITCO = Selective hCAR Activator CYP2B6 CYP3A4 Faucette S. et al. JPET 2006
  7. 7. CYP2B6 CYP3A4 Faucette S. et al., JPET 2007
  8. 8. Asymmetric Cross-talk Between PXR and CAR PXR RXR CAR RXR XREM PXRE ER6 PBREM XREM CYP3A4 CYP2B6 Faucette S. et al., JPET 2006
  9. 9. Ritonavir affects the activity of CYP3A4/2B6 Faucette et al., DMD 2004
  10. 10. Potential Clinical Benefit of Differential Regulation of CYP2B6 and CYP3A4 by hCAR dechloroethylCPA (neurotoxic) CYP3A4 CYP2B6 4-hydroxyCPA CAR activator cyclophosphamide phosphoramide mustard + acrolein (therapeutically active) spontaneous Ritonavir + _
  11. 11. LC-Ms/MS chromatograms of CPA & 4-OHCP
  12. 12. Project Aims <ul><li>Identify selective CAR activators as drug targets for preferential induction of CYP2B over CYP3A in vitro </li></ul><ul><li>Evaluate ritonavir and its analogs as alternative drug targets in modulating CYP2B6 induction and CYP3A4 inhibition </li></ul><ul><li>Examine the effects of selective CYP2B6 inducers on the biotransformation of CPA in vitro </li></ul><ul><li>Validate CAR activator-mediated pharmacokinetic changes of CPA in humanized CAR animal model </li></ul>
  13. 13. Acknowledgements <ul><li>Lab Members </li></ul><ul><ul><li>Duan Wang </li></ul></ul><ul><ul><li>Dr. Haishan Li </li></ul></ul><ul><ul><li>Dr. Linhao Li </li></ul></ul><ul><ul><li>Dr. Leslie M. Tompkins </li></ul></ul><ul><ul><li>Antonia Tolson </li></ul></ul><ul><li>Previous lab members: </li></ul><ul><ul><li>Dr. Stephanie Faucette </li></ul></ul><ul><ul><li>Dr. Cornelia Smith </li></ul></ul><ul><li>Collaborators: </li></ul><ul><li>Dr. Michael Colvin </li></ul><ul><li>Dr. Douglas Ross </li></ul><ul><li>Funding Support </li></ul><ul><li>GCC Seed Grant </li></ul><ul><li>NIH </li></ul>