Impact of <i>CYP2C9</i> amino acid polymorphisms on glyburide kinetics and on the insulin and glucose response in healthy volunteers

Kirchheiner, Julia; Brockmöller, Jürgen; Meineke, Ingolf; Bauer, Steffen; Rohde, Wolfgang; Meisel, Christian; Roots, Ivar

doi:10.1067/mcp.2002.122476

Cited by 229 publications

(238 citation statements)

References 26 publications

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“…Interestingly, however, under chronic treatment, glibenclamide progressively and selectively accumulates in islets and is slowly cleared from islets on drug withdrawal (21). Additionally, there are large interindividual variations in the pharmacodynamics and pharmacokinetics of glibenclamide, which are furthermore greatly influenced by genetic polymorphisms of the cytochrome P-450 2C9 system (24). Hence, carriers of certain CYP2C9 genotype variants show markedly reduced clearance rates of glibenclamide, resulting in severalfold-elevated serum concentrations of the drug (24).…”

Section: Discussionmentioning

confidence: 99%

“…At a first glance, it would seem that the submicromolar therapeutical concentrations of (23,24) would not be sufficient to affect the islet CPT system in diabetic patients (Fig. 2).…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, there are large interindividual variations in the pharmacodynamics and pharmacokinetics of glibenclamide, which are furthermore greatly influenced by genetic polymorphisms of the cytochrome P-450 2C9 system (24). Hence, carriers of certain CYP2C9 genotype variants show markedly reduced clearance rates of glibenclamide, resulting in severalfold-elevated serum concentrations of the drug (24). There are also several important drug interactions that may additionally elevate glibenclamide serum levels, which may be significant in elderly diabetic patients who are often on multiple medications and have impaired drug metabolism (23,27).…”

Section: Discussionmentioning

confidence: 99%

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Glibenclamide inhibits islet carnitine palmitoyltransferase 1 activity, leading to PKC-dependent insulin exocytosis

Lehtihet

Welsh

Berggren

et al. 2003

American Journal of Physiology-Endocrinology and Metabolism

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Hypoglycemic sulfonylureas such as glibenclamide have been widely used to treat type 2 diabetic patients for 40 yr, but controversy remains about their mode of action. The widely held view is that they promote rapid insulin exocytosis by binding to and blocking pancreatic β-cell ATP-dependent K+ (KATP) channels in the plasma membrane. This event stimulates Ca2+ influx and sets in motion the exocytotic release of insulin. However, recent reports show that >90% of glibenclamide-binding sites are localized intracellularly and that the drug can stimulate insulin release independently of changes in KATP channels and cytoplasmic free Ca2+. Also, glibenclamide specifically and progressively accumulates in islets in association with secretory granules and mitochondria and causes long-lasting insulin secretion. It has been proposed that nutrient insulin secretagogues stimulate insulin release by increasing formation of malonyl-CoA, which, by blocking carnitine palmitoyltransferase 1 (CPT-1), switches fatty acid (FA) catabolism to synthesis of PKC-activating lipids. We show that glibenclamide dose-dependently inhibits β-cell CPT-1 activity, consequently suppressing FA oxidation to the same extent as glucose in cultured fetal rat islets. This is associated with enhanced diacylglycerol (DAG) formation, PKC activation, and KATP-independent glibenclamide-stimulated insulin exocytosis. The fat oxidation inhibitor etomoxir stimulated KATP-independent insulin secretion to the same extent as glibenclamide, and the action of both drugs was not additive. We propose a mechanism in which inhibition of CPT-1 activity by glibenclamide switches β-cell FA metabolism to DAG synthesis and subsequent PKC-dependent and KATP-independent insulin exocytosis. We suggest that chronic CPT inhibition, through the progressive islet accumulation of glibenclamide, may explain the prolonged stimulation of insulin secretion in some diabetic patients even after drug removal that contributes to the sustained hypoglycemia of the sulfonylurea.

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Section: Discussionmentioning

confidence: 99%

“…At a first glance, it would seem that the submicromolar therapeutical concentrations of (23,24) would not be sufficient to affect the islet CPT system in diabetic patients (Fig. 2).…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Glibenclamide inhibits islet carnitine palmitoyltransferase 1 activity, leading to PKC-dependent insulin exocytosis

Lehtihet

Welsh

Berggren

et al. 2003

American Journal of Physiology-Endocrinology and Metabolism

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“…32 The LD block including CYP2C9 identified by the software program Sweep spanned 16 polymorphisms and revealed eight haplotypes. Although only three of the polymorphisms were identical to those analysed in our sample, this data set revealed the haplotypes H7 to H10 having comparable frequencies (23,17,15 and 6%) as with our polymorphism set. The remaining four haplotypes amount to 40% and were subhaplotypes of H6.…”

Section: Haplotype-phenotype Associationmentioning

confidence: 88%

“…Torsemide clearance was greatly reduced in carriers of the CYP2C9*3 variant but not in carriers of the CYP2C9*2 variant in accordance with in vitro findings. 2,19,21,22 Torsemide may therefore be a valuable CYP2C9 probe drug with specific properties compared to the other commonly used substrates tolbutamide, 23 warfarin [24][25][26] or losartan. 27 Phenotyping unselected samples has lead to the identification of functionally relevant genetic polymorphisms.…”

Section: Introductionmentioning

confidence: 99%

Genetic variation at the CYP2C locus and its association with torsemide biotransformation

et al. 2006

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In 97 unselected volunteers and two additional homozygous carriers of CYP2C9*3, we investigated the oral clearance of torsemide in relation to 37 polymorphisms at the CYP2C gene locus. Torsemide total oral clearance was linearly associated with the number of CYP2C9*3 alleles (geometric mean: 59, 40 and 20 ml/min in carriers of no, one and two alleles) and so were the methyl-and ring-hydroxylation but not the carboxylation clearance. Haplotypes including the CYP2C9*3 allele were similarly associated with the clearances but no other variant and no haplotype not including the CYP2C9*3 variant. The extended haplotype length (EHL) of the CYP2C9 haplotypes was positively associated with higher activity of the gene product. Torsemide total oral clearance was predictable with r 2 ¼ 82.1% using plasma concentrations at 0.5, 1, 2 and 24 h. In conclusion, torsemide's biotransformation strongly depended on the CYP2C9*3 variant but no other. Higher clearance CYP2C9 haplotypes appear to be evolutionarily selected.

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Drug-Drug Interactions Among Elderly Patients Hospitalized for Drug Toxicity

Juurlink¹

2003

JAMA

655

425

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DVERSE DRUG EVENTS AFFECTmillions of patients each year and are responsible for up to 5% of hospital admissions. 1,2 They also pose an enormous financial burden, with an estimated cost of more than $16000 per hospitalization. 3 While some adverse drug events are unpredictable (such as anaphylaxis from an unrecognized allergy), many others can be anticipated and prevented.Drug-drug interactions are a particularly important type of adverse drug event because they are often predictable based on previous reports, clinical studies, and an understanding of pharmacologic principles. Some adverse drug events have life-threatening consequences and may prompt the removal of popular medications from the marketplace. 4-10 Such drastic measures are probably justifiable because clinicians are often unaware of serious drug-drug interactions. [11][12][13][14][15] Moreover, the computer systems intended to help avert dangerous drug combinations fail to detect up to a third of drugdrug interactions, while frequently alerting pharmacists to trivial or nonspecific interactions. 14,16,17 Little information is available about the epidemiology of drug-drug interactions in clinical practice, and most of the evidence is derived from case reports, volunteer studies, or investigations of potential drug-drug interactions in hospitalized patients. [18][19][20][21][22][23] No studies to date have examined clinical outcomes of

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Impact of CYP2C9 amino acid polymorphisms on glyburide kinetics and on the insulin and glucose response in healthy volunteers

Abstract: Carriers of the CYP2C9 variant *3 had decreased oral clearances of glyburide. This confirms that glyburide is metabolized by CYP2C9. Corresponding differences in insulin plasma levels indicated that dose adjustment based on CYP2C9 genotype may improve antidiabetic treatment.

Cited by 229 publications

References 26 publications

Glibenclamide inhibits islet carnitine palmitoyltransferase 1 activity, leading to PKC-dependent insulin exocytosis

Glibenclamide inhibits islet carnitine palmitoyltransferase 1 activity, leading to PKC-dependent insulin exocytosis

Genetic variation at the CYP2C locus and its association with torsemide biotransformation

Drug-Drug Interactions Among Elderly Patients Hospitalized for Drug Toxicity

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