ArticleBritish journal of clinical pharmacology2007
Identification of the human cytochromes P450 catalysing the rate-limiting pathways of gliclazide elimination.
Article in British journal of clinical pharmacology, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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15 citing papers in PubMed.
- Physiologically based pharmacokinetic (PBPK) modeling of gliclazide for different genotypes of CYP2C9 and CYP2C19.Archives of pharmacal research · 2025Article
- Effects of CYP2C9 and CYP2C19 genetic polymorphisms on the pharmacokinetics and pharmacodynamics of gliclazide in healthy subjects.Archives of pharmacal research · 2023Article
- CYP2C19 Loss-of-function Polymorphisms are Associated with Reduced Risk of Sulfonylurea Treatment Failure in Chinese Patients with Type 2 Diabetes.Clinical pharmacology and therapeutics · 2022Article
- Effect ofCurrent drug metabolism · 2022Article
- Interaction between Omeprazole and Gliclazide in Relation to CYP2C19 Phenotype.Journal of personalized medicine · 2021Article
- Discovery of Orally Active and Nonsteroidal Farnesoid X Receptor (FXR) Antagonist with Propensity for Accumulation and Responsiveness in Ileum.ACS medicinal chemistry letters · 2021Article
- Pharmacogenetics of hypoglycemia associated with sulfonylurea therapy in usual clinical care.The pharmacogenomics journal · 2020Article
- Pharmacogenomics of CYP2C9: Functional and Clinical Considerations.Journal of personalized medicine · 2017Review
- CYP2C93 variant is associated with antidiabetes efficacy of gliclazide in Chinese type 2 diabetes patients.Journal of diabetes investigation · 2016Article
- Applications of CYP450 testing in the clinical setting.Molecular diagnosis & therapy · 2013Review
- Pharmacogenetics of oral antidiabetic drugs.International journal of endocrinology · 2013Review
- Metabolic activation of clopidogrel: in vitro data provide conflicting evidence for the contributions of CYP2C19 and PON1.Therapeutic advances in drug safety · 2011Review
- Mild hypoglycaemic attacks induced by sulphonylureas related to CYP2C9, CYP2C19 and CYP2C8 polymorphisms in routine clinical setting.European journal of clinical pharmacology · 2011Article
- Pharmacogenetics in diabetes.Current diabetes reports · 2009Review
- Effects of St John's wort and CYP2C9 genotype on the pharmacokinetics and pharmacodynamics of gliclazide.British journal of pharmacology · 2008Article
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7 authors.
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Abstract
aimsTo identify the human cytochrome P450 (CYP) enzymes responsible for the formation of the 6beta-hydroxy (6beta-OHGz), 7beta-hydroxy (7beta-OHGz) and hydroxymethyl (MeOH-Gz) metabolites of gliclizide (Gz).
methods6beta-OHGz, 7beta-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.
resultsMicrosomes from six human livers converted Gz to its 6beta-OHGz, 7beta-OHGz, and MeOH-Gz metabolites, with respective mean (+/- SD) K(m) values of 461 +/- 139, 404 +/- 143 and 334 +/- 75 microm and mean V(max) values of 130 +/- 55, 82 +/- 31 and 268 +/- 115 pmol min(-1) mg(-1), respectively. V(max)/K(m) ratios for the microsomal reactions parallelled relative metabolite formation in vivo. Sulfaphenazole inhibited microsomal 6beta-OHGz, 7beta-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 6beta-OHGz and 7beta-OHGz.
conclusionTaken 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.
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