Rosiglitazone Metabolism in Human Liver Microsomes Using a Substrate Depletion Method.
Article Details
- CitationCopy to clipboard
Bazargan M, Foster DJ, Davey AK, Muhlhausler BS
Rosiglitazone Metabolism in Human Liver Microsomes Using a Substrate Depletion Method.
Drugs R D. 2017 Mar;17(1):189-198. doi: 10.1007/s40268-016-0166-4.
- PubMed ID
- 28074333 [ View in PubMed]
- 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 microM 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. CONCLUSION: 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.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Rosiglitazone Cytochrome P450 2C8 Protein Humans UnknownSubstrateInhibitorDetails Rosiglitazone Cytochrome P450 2C9 Protein Humans UnknownSubstrateInhibitorDetails Rosiglitazone Cytochrome P450 2E1 Protein Humans UnknownSubstrateDetails