title: Rosiglitazone Metabolism in Human Liver Microsomes Using a Substrate Depletion Method.
abstract: BACKGROUND
  Elimination of rosiglitazone in humans is via hepatic metabolism. The existing studies suggest that CYP2C8 is the major enzyme responsible, with a minor contribution from CYP2C9; however, other studies suggest the involvement of additional cytochrome P450 enzymes and metabolic pathways. Thus a full picture of rosiglitazone metabolism is unclear.
  
  
  OBJECTIVE
  This study aimed to improve the current understanding of potential drug-drug interactions and implications for therapy by evaluating the kinetics of rosiglitazone metabolism and examining the impact of specific inhibitors on its metabolism using the substrate depletion method.
  
  
  METHODS
  In vitro oxidative metabolism of rosiglitazone in human liver microsomes obtained from five donors was determined over a 0.5-500 µM substrate range including the contribution of CYP2C8, CYP2C9, CYP3A4, CYP2E1, and CYP2D6.
  
  
  RESULTS
  The maximum reaction velocity was 1.64 ± 0.98 nmol·mg-1·min-1. The CYP2C8 (69 ± 20%), CYP2C9 (42 ± 10%), CYP3A4 (52 ± 23%), and CEP2E1 (41 ± 13%) inhibitors all significantly inhibited rosiglitazone metabolism.
  
  
  CONCLUSIONS
  The results suggest that other cytochrome P450 enzymes, including CYP2C9, CYP3A4, and CEP2E1, in addition to CYP28, also play an important role in the metabolism of rosiglitazone. This example demonstrates that understanding the complete metabolism of a drug is important when evaluating the potential for drug-drug interactions and will assist to improve the current therapeutic strategies.
authors.affiliation: Sansom Institute, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia. Maryam.Bazargan@mymail.unisa.edu.au.|School of Nursing and Midwifery, Flinders University, Adelaide, South Australia, Australia. Maryam.Bazargan@mymail.unisa.edu.au.
authors.forename: Maryam
authors.initials: M
authors.lastname: Bazargan
authors.affiliation: Sansom Institute, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia.
authors.forename: David J R
authors.initials: DJ
authors.lastname: Foster
authors.affiliation: Sansom Institute, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia.|Menzies Health Institute Queensland and School of Pharmacy, Griffith University, Brisbane, Queensland, Australia.
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Davey
authors.affiliation: Sansom Institute, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia.|FOODplus Research Centre, School of Agriculture, Food and Wine, The University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Beverly S
authors.initials: BS
authors.lastname: Muhlhausler
mesh_terms: D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007700:Kinetics; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D000077154:Rosiglitazone; D013329:Structure-Activity Relationship; D045162:Thiazolidinediones / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D045162:Thiazolidinediones; D000077154:Rosiglitazone; D003577:Cytochrome P-450 Enzyme System