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CYP2B6 and Drug Interactions FDA Advisory Committee for Pharmaceutical Sciences Clinical Pharmacology Subcommittee Novem

CYP2B6 and Drug Interactions FDA Advisory Committee for Pharmaceutical Sciences Clinical Pharmacology Subcommittee November 18 th , 2003. Zeruesenay Desta PhD David A Flockhart MD, PhD Indiana University School of Medicine . Outline. CYP2B6 expression CYP2B6 substrates In vitro In vivo?

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CYP2B6 and Drug Interactions FDA Advisory Committee for Pharmaceutical Sciences Clinical Pharmacology Subcommittee Novem

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  1. CYP2B6 and Drug InteractionsFDA Advisory Committeefor Pharmaceutical SciencesClinical Pharmacology SubcommitteeNovember 18th, 2003. Zeruesenay Desta PhD David A Flockhart MD, PhD Indiana University School of Medicine

  2. Outline • CYP2B6 expression • CYP2B6 substrates • In vitro • In vivo? • CYP2B6 inhibitors • CYP inducers • Relevant in vivo data

  3. CYP2B6 expression: Late 1990s • Low level of protein expression • Minor component of the total hepatic CYPs (<1% of total P450 in the liver) • Thought to play a relatively minor role in human drug metabolism

  4. CYP2B6 Expression: Initial Studies

  5. CYP2B6 Expression: Recent Studies

  6. CYP2B6 Expression: 2003 • New mono- and polyclonal antibodies of higher sensitivity and specificity for CYP2B6 protein immuno-quantification: • Greater frequency of detection (almost in all human livers tested) • Higher protein quantities: • Average: ~6% of the total liver CYP450 content • Absolute maximum amounts: up to 25 to 43.5%

  7. Human metabolism of efavirenz (Ward et al., J Pharmacol Exp Ther 2003)

  8. CYP2B6 catalyses the metabolism of efavirienz (1µM)

  9. Effect of rifampin on efavirenz in healthy volunteers

  10. CYP2B6 Catalyses metabolism of an efavirenz analog: DPC 963 Drug Metab Dispos. 2003 Jan;31(1):122-32.

  11. CYP2B6 is a low affinity catalyst of S-mephenytoin metabolism to Nirvanol Heyn et al Drug Metab Dispos 1996;24:948-954 Km = 564µM

  12. N-Demethylation of S-mephenytoin (200µM) by CYP2C9 and CYP2B6 Ko, Desta and Flockhart. Drug Metab Dispos 1998;26(8):775-778

  13. Human Metabolism of Mephenytoin

  14. R-mephenytoin as CYP2B6 substrate probe?

  15. Inhibitors: Antidepressants (e.g. paroxetine and sertraline) Antiretrovirals (e.g. nelfinavir and ritonavir) Ticlopidine and clopidogrel ThioTEPA Inhibitors of CYP2B6

  16. ThioTEPA is a specific cytochrome P450 inhibitor in vitro IC50 5µM

  17. Inhibition of CYP2B6 by thioTEPA Ki=4.8 ± 0.3 µM (HLMs) Ki=6.2 ± 0.7 µM (CYP2B6) ThioTEPA therapeutic concentration: 1.1-18.6 µM

  18. Cyclophosphamide activation

  19. Effect of thioTEPA on the PK of CPA • (Huitema et al. Cancer Chemother Pharmacol 2000;46:119-127)

  20. Inducers of CYP2B6 Rifampin Hyperforin Phenobarbital Ritonavir Phenytoin Carbamazepine HMG-CoA reductase inhibitors Nevirapine Efavirenz Clotrimazole Artemisinin

  21. Conclusions • CYP2B6 is a significant contributor to hepatic CYP expression • The number of substrate drugs for CYP2B6 is growing rapidly • Efavirenz and buproprion are specific in vitro probes for CYP2B6 activity • ThioTEPA is a specific in vitro inhibitor of CYP2B6 • No valuable, specific inhibitors of CYP2B6 in vivo have been demonstrated to date • Efavirenz is a potentially valuable in vivo probe for CYP2B6 activity

  22. Effect of rifampin on efavirenz in healthy volunteers

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