Identification of the human cytochromes P450 catalysing the rate-limiting pathways of gliclazide elimination

David J. Elliot and Suharjono and Benjamin C. Lewis and Elizabeth M. J. Gillam and Donald J. Birkett and Annette S. Gross and John O. Miners (2007) Identification of the human cytochromes P450 catalysing the rate-limiting pathways of gliclazide elimination. British Journal Clinical Pharmacology, 10 (64). pp. 450-457. ISSN 1365-2125

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Official URL: http://onlinelibrary.wiley.com/doi/10.1111/j.1365-...

Abstract

Aims To identify the human cytochrome P450 (CYP) enzymes responsible for the formation of the 6β-hydroxy (6β-OHGz), 7β-hydroxy (7β-OHGz) and hydroxymethyl (MeOH-Gz) metabolites of gliclizide (Gz). Methods 6β-OHGz, 7β-OHGz and MeOH-Gz formation by human liver microsomes and a panel of recombinant human P450s was measured using a high-performance liquid chromatography procedure, and the kinetics of metabolite formation was determined for each pathway. Effects of prototypic CYP enzyme selective inhibitors were characterized for each of the microsomal metabolic pathways. Results Microsomes from six human livers converted Gz to its 6β-OHGz, 7β-OHGz, and MeOH-Gz metabolites, with respective mean (± SD) Km values of 461 ± 139, 404 ± 143 and 334 ± 75 µm and mean Vmax values of 130 ± 55, 82 ± 31 and 268 ± 115 pmol min−1 mg−1, respectively. Vmax/Km ratios for the microsomal reactions parallelled relative metabolite formation in vivo. Sulfaphenazole inhibited microsomal 6β-OHGz, 7β-OHGz and MeOH-Gz formation by 87, 83 and 64%, respectively, whereas S-mephenytoin caused significant inhibition (48%) of only MeOH-Gz formation. Recombinant CYP2C9, CYP2C18 and CYP2C19 catalysed all hydroxylation pathways, whereas CYP2C8 formed only 6β-OHGz and 7β-OHGz. Conclusion Taken together, the results indicate that CYP2C9 is the major contributor to Gz metabolic clearance, although CYP2C19 may also be involved in MeOH-Gz formation (the major metabolic pathway). Factors known to influence CYP2C9 activity will provide the main source of variability in Gz pharmacokinetics.

Item Type: Article
Uncontrolled Keywords: CYP2C18, CYP2C19, CYP2C9, cytochrome P450, gliclazide, reaction phenotyping
Subjects: R Medicine
R Medicine > RS Pharmacy and materia medica
R Medicine > RS Pharmacy and materia medica > RS1-441 Pharmacy and materia medica
Divisions: 05. Fakultas Farmasi > Farmasi Klinis
Peer Review
Creators:
CreatorsNIM/NIDN
David J. ElliotUNSPECIFIED
Suharjonosuharjono@ff.unair.ac.id
Benjamin C. LewisUNSPECIFIED
Elizabeth M. J. GillamUNSPECIFIED
Donald J. BirkettUNSPECIFIED
Annette S. GrossUNSPECIFIED
John O. MinersUNSPECIFIED
Depositing User: Mr M. Fuad Sofyan
Date Deposited: 24 Apr 2017 18:47
Last Modified: 24 Apr 2017 18:47
URI: http://repository.unair.ac.id/id/eprint/56659
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