CYP2B6andDrugInteractionsFDAAdvisoryCommitteefor.pptVIP

CYP2B6 and Drug InteractionsFDA Advisory Committee for Pharmaceutical SciencesClinical Pharmacology SubcommitteeNovember 18th, 2003. Zeruesenay Desta PhD David A Flockhart MD, PhD Indiana University School of Medicine Outline CYP2B6 expression CYP2B6 substrates In vitro In vivo? CYP2B6 inhibitors CYP inducers Relevant in vivo data 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 CYP2B6 Expression: Initial Studies Detection (%) Pmol/mg protein (range) References 13/13 (100%)** ? Yamano et al 1989 12/12 (100%)* ? Forrester et al., 1992 12/14 (86%), Thai ? Kirby et al 1993 12/50 (24%) 1.4?1.5 (0-7) Mimura et al 1993 9/30 (30%) (Japanese) ?0.25 (0-2) Shimada et al 1994 26/30 (87%), Caucasian 1.0 (0-2.5) Shimada et al 1994 2/10 (20%) ? Baker et al 1995 ?/40, Japanese 0.14?0.62 Guengerich et al 1995 ?/32, Caucasian 1.4?1.8 Guengerich et al 1995 ?/16 3 (0-17) Imaoka et al 1996 8/30 (27%) ? Boobis et al 1996 High level in Thai ? Kim et al 1997 7/10 (70%) 19.36?23.9) Tateishi et al 1997 2/10 (20%) 2.65?5.94 Tateishi et al 1997 6/30 (20%) ? Edwards et al 1998 CYP2B6 Expression: Recent Studies Detection (%) Pmol/mg protein (range) Variability References 17/17 (100) 15?21 (0.5-70) 247-fold Code et al. 1997 24/26 (92) 10.9?9.5 (0-28) ? Yang et al., 1998 19/19 (100) 9.77?17.6 (0.7-71.1) 107-fold Ekins et al 1998 28/28 (100) 24.9 ?18.2 (2-82) 41-fold Stresser et al, 1999 43/48 (90) 1.7 (0.4-8, n=43 livers) 20 Gervot et al 1999 15/16 (94) ? 100-fold (n=15) Faucette et al 2000 12/12 (100) 44.6 (1.5-148.4) 99-fold Hesse et al 2000 136/136 (100) 16.9?16.6 (0.5-95.5) 191-fold Lang et al. 2001 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) Hi