Glyburide and glimepiride pharmacokinetics in subjects with different <i>CYP2C9</i> genotypes

Niemi, Mikko; Cascorbi, Ingolf; Timm, Ramona; Kroemer, Heyo K.; Neuvonen, Pertti J.; Kivistö, Kari T.

doi:10.1067/mcp.2002.127495

Cited by 158 publications

(129 citation statements)

References 16 publications

(28 reference statements)

Supporting

Mentioning

122

Contrasting

Order By: Relevance

“…CYP2C9 genotyping for C430T (Arg144Cys; *2) and A1075C (Ile359-Leu; *3) was performed as described previously. 34 CYP2C19 was genotyped accordingly for the deleterious splice-site variant G681A (*2), with 4 pmol of the forward primer 5 0 -AAC CAG AGC TTG GCA TAT TG, 4 pmol of the reverse primer 5 0 -CGC TAA GTA ATT TGT TAT GGG TTT, 2 pmol of the anchor probe 5 0 -AGT GGG AAA ATT ATT GCA TAT CTA AGA GAA AAC-LC Red640 and 2 pmol of the sensor probe 5 0 -GGG TTT CCG GGA AAT AAT CAA Tfluorescein-isothiocyanat (TIB Molbiol, Berlin, Germany). PCR conditions were 75 cycles of 2 s at 951C, 12 s at 551C, and 15 s at 721C (temperature slope 201C/s).…”

Section: Dna Extraction and Allelic Discriminationmentioning

confidence: 99%

Association of cyclophosphamide pharmacokinetics to polymorphic cytochrome P450 2C19

et al. 2005

View full text Add to dashboard Cite

Cyclophosphamide (CP), a widely used cytostatic, is metabolized by polymorphic drug metabolizing enzymes particularly cytochrome P450 (CYP) enzymes. Its side effects and clinical efficacy exhibit a broad interindividual variability, which might be due to differences in pharmacokinetics. CP-kinetics were determined in 60 patients using a global and a population pharmacokinetic model considering functionally relevant polymorphisms of CYP2B6, CYP2C9, CYP2C19, CYP3A5, and GSTA1. Moreover, metabolic ratios were calculated for selected CP metabolites, analyzed by 31 P-NMR-spectroscopy. Analysis of variance revealed that the CYP2C19*2 genotype influenced significantly pharmacokinetics of CP at doses p1000 mg/m 2 , whereas there was no evidence of an association of other genotypes to CP elimination or clearance. Mean (7SD) CP elimination constants k e (h À1 ) were 0.10970.025 in 44 CYP2C19*1/*1 subjects, 0.08870.018 in 13 CYP2C19*1/*2, and 0.07670.014 in three inactive CYP2C19*2/*2 carriers (P ¼ 0.009). At CP doses higher than 1000 mg/m 2 , a significantly increase of elimination was observed (P ¼ 0.001), possibly due to CYP induction. Further studies should link these findings with the clinical outcome.

show abstract

Section: Dna Extraction and Allelic Discriminationmentioning

confidence: 99%

Association of cyclophosphamide pharmacokinetics to polymorphic cytochrome P450 2C19

et al. 2005

View full text Add to dashboard Cite

show abstract

“…The two major metabolites of GLY in urine, which are also pharmacologically active [8][9], are 4-transhydroxy glyburide (M1) and 3-cishydroxy glyburide (M2) [10][11] (Fig 1). There are conflicting data in the literature regarding the identity of the cytochrome P450s (CYPs) involved in the metabolism of GLY [12][13].…”

Section: Introductionmentioning

confidence: 99%

Validation of a sensitive LC–MS assay for quantification of glyburide and its metabolite 4-transhydroxy glyburide in plasma and urine: An OPRU Network study

Kirby

Hébert

Easterling

et al. 2007

Journal of Chromatography B

View full text Add to dashboard Cite

Glyburide (glibenclamide, INN), a second generation sulfonylurea is widely used in the treatment of gestational diabetes mellitus (GDM). None of the previously reported analytical methods provide adequate sensitivity for the expected sub-nanogram/mL maternal and umbilical cord plasma concentrations of glyburide during pregnancy. We developed and validated a sensitive and low sample volume liquid chromatographic-mass spectrometric (LC-MS) method for simultaneous determination of glyburide (GLY) and its metabolite, 4-transhydroxy glyburide (M1) in human plasma (0.5 ml) or urine (0.1 ml). The limits of quantitation (LOQ) for GLY and M1 in plasma were 0.25 and 0.40 ng/mL, respectively whereas it was 1.06 ng/mL for M1 in urine. As measured by quality control samples, precision (% coefficient of variation) of the assay was < 15% whereas the accuracy (% deviation from expected) ranged from −10.1-14.3%. We found that the GLY metabolite, M1 is excreted in the urine as the glucuronide-conjugate.

show abstract

“…CYP2C9 has been reported to catalyze approximately 20% of P450-mediated drug oxidation reactions (Shimada et al, 1994;Rendic and Dicarlo, 1997;Miners and Birkett, 1998), including agents such as nonsteroidal anti-inflammatory drugs, tolbutamide, losartan, and the narrow therapeutic index drugs warfarin and phenytoin (Rettie et al, 1992;Stearns et al, 1995;Tracy et al, 1995;Bajpai et al, 1996;Miners and Birkett, 1996;Hamman et al, 1997;Niemi et al, 2002;Yan et al, 2005). To date, 30 CYP2C9 allelic variants located within the coding region have been reported (http://www.imm.ki.SE/CYPalleles).…”

mentioning

confidence: 99%

Differential Genotype Dependent Inhibition of CYP2C9 in Humans

Kumar

Brundage²,

Oetting³

et al. 2008

Drug Metab Dispos

View full text Add to dashboard Cite

ABSTRACT:The effects of genetic polymorphisms in drug-metabolizing enzymes (e.g., CYP2C9*3) on drug clearance have been well characterized but much less is known about whether these polymorphisms alter susceptibility to drug-drug interactions. Previous in vitro work has demonstrated that genotype-dependent inhibition of CYP2C9 mediated flurbiprofen metabolism, suggesting the possibility of genotype-dependent inhibition interactions in vivo. In the current study, flurbiprofen was used as a probe substrate and fluconazole as a prototypical inhibitor to investigate whether genotype-dependent inhibition of CYP2C9 occurs in vivo. From 189 healthy volunteers who were genotyped for CYP2C9 polymorphisms, 11 control subjects (CYP2C9*1/*1), 9 heterozygous and 2 homozygous for the CYP2C9*3 allele participated in the pharmacokinetic drug interaction study. Subjects received a single 50-mg oral dose of flurbiprofen alone or after administration of either 200 or 400 mg of fluconazole for 7 days using an open, randomized, crossover design. Flurbiprofen and fluconazole plasma concentrations along with flurbiprofen and 4-hydroxyflurbiprofen urinary excretion were monitored. Flurbiprofen apparent oral clearance differed significantly among the three genotype groups (p < 0.05) at baseline but not after pretreatment with 400 mg of fluconazole for 7 days. Changes in flurbiprofen apparent oral clearance after fluconazole coadministration were gene dose-dependent, with virtually no change occurring in *3/*3 subjects. Analysis of fractional clearances suggested that the fraction metabolized by CYP2C9, as influenced by genotype, determined the degree of drug interaction observed. In summary, the presence of CYP2C9*3 alleles (either one or two alleles) can alter the degree of drug interaction observed upon coadministration of inhibitors.The cytochrome P450 (P450) superfamily of enzymes plays an important role in the oxidation of numerous xenobiotics, with CYP2C9 accounting for 10 to 20% of the P450 protein content in human liver. CYP2C9 has been reported to catalyze approximately 20% of P450-mediated drug oxidation reactions (Shimada et al., 1994;Rendic and Dicarlo, 1997;Miners and Birkett, 1998), including agents such as nonsteroidal anti-inflammatory drugs, tolbutamide, losartan, and the narrow therapeutic index drugs warfarin and phenytoin (Rettie et al., 1992;Stearns et al., 1995;Tracy et al., 1995;Bajpai et al., 1996;Miners and Birkett, 1996;Hamman et al., 1997;Niemi et al., 2002;Yan et al., 2005). To date, 30 CYP2C9 allelic variants located within the coding region have been reported (http://www.imm.ki.SE/CYPalleles). In particular, the *3 allele (Ile 359 Leu), which is expressed at an allele frequency of 15% (Lee et al., 2002), results in significantly reduced oral clearance for several CYP2C9 substrates (Aithal et al., 1999;Lee et al., 2003b;Vianna-Jorge et al., 2004;Guo et al., 2005;Perini et al., 2005) and has been associated with an increased frequency of adverse events after warfarin or phenytoin administration (Kidd et al., ...

show abstract

Glyburide and glimepiride pharmacokinetics in subjects with different CYP2C9 genotypes

Abstract: Genetic polymorphisms of CYP2C9 markedly affect the pharmacokinetics of both glyburide and glimepiride. The influence of the CYP2C9*3 variant allele on glyburide and glimepiride pharmacokinetics may be clinically significant.

Cited by 158 publications

References 16 publications

Association of cyclophosphamide pharmacokinetics to polymorphic cytochrome P450 2C19

Association of cyclophosphamide pharmacokinetics to polymorphic cytochrome P450 2C19

Validation of a sensitive LC–MS assay for quantification of glyburide and its metabolite 4-transhydroxy glyburide in plasma and urine: An OPRU Network study

Differential Genotype Dependent Inhibition of CYP2C9 in Humans

Contact Info

Product

Resources

About