title: Comprehensive evaluation of liver microsomal cytochrome P450 3A (CYP3A) inhibition: comparison of cynomolgus monkey and human.
abstract: 1. Members of the cytochrome P450 3A (CYP3A) subfamily metabolize numerous compounds and serve as the loci of drug-drug interactions (DDIs). Because of high amino acid sequence identity with human CYP3A, the cynomolgus monkey has been proposed as a model species to support DDI risk assessment. 2. Therefore, the objective of this study was to evaluate 35 known inhibitors of human CYP3A using human (HLM) and cynomolgus monkey (CLM) liver microsomes. Midazolam was employed as substrate to generate IC50values (concentration of inhibitor rendering 50% inhibition) in the absence and presence of a preincubation (30 mins) with NADPH. 3. In the absence of preincubation, the IC50values generated with CLM were similar to those obtained with HLM (86% within 2-fold; 100% within 3-fold difference). However, significant differences (up to 48-fold) in preincubation IC50were observed with 17% of the compounds (raloxifene, bergamottin, nicardipine, mibefradil, ritonavir, and diltiazem). 4. Our results indicate that in most cases the cynomolgus monkey can be a viable DDI model. However, significant species differences in time-dependent CYP3A inhibition can be observed for some compounds. In the case of raloxifene, such a difference can be ascribed to a specific CYP3A4 amino acid residue.
authors: a Bristol-Myers Squibb , Wallingford , CT , USA.
authors: Zuzana E
authors: ZE
authors: Haarhoff
authors: b Pfizer Global Research and Development , Groton , CT , USA , and.
authors: Melissa A
authors: MA
authors: Kramer
authors: a Bristol-Myers Squibb , Wallingford , CT , USA.
authors: Tatyana A
authors: TA
authors: Zvyaga
authors: a Bristol-Myers Squibb , Wallingford , CT , USA.
authors: Jun
authors: J
authors: Zhang
authors: c Biocon Bristol-Myers Squibb Research and Development Center, Syngene International Limited , Bangalore , Karnataka , India.
authors: Priyadeep
authors: P
authors: Bhutani
authors: c Biocon Bristol-Myers Squibb Research and Development Center, Syngene International Limited , Bangalore , Karnataka , India.
authors: Murali
authors: M
authors: Subramanian
authors: b Pfizer Global Research and Development , Groton , CT , USA , and.
authors: A David
authors: AD
authors: Rodrigues
mesh_terms: D000818:Animals; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D004110:Diltiazem; D004347:Drug Interactions; D006801:Humans; D007700:Kinetics; D008252:Macaca fascicularis; D008862:Microsomes, Liver / Q000378:metabolism; D008874:Midazolam / Q000378:metabolism / Q000494:pharmacology; D008954:Models, Biological
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D051544:Cytochrome P-450 CYP3A; D004110:Diltiazem; D008874:Midazolam
keywords: CYP3A; Cynomolgus monkey; DDI model; drug–drug interaction; in vitro–in vivo extrapolation; time-dependent inhibition