ROLE OF CYP2C9 AND ITS VARIANTS (CYP2C9<sup>*</sup>3 AND CYP2C9<sup>*</sup>13) IN THE METABOLISM OF LORNOXICAM IN HUMANS

Guo, Yingjie; Zhang, Yifan; Wang, Ying; Chen, Xiaoyan; Si, Daoyuan; Zhong, Dafang; Fawcett, James P.; Zhou, Hui

doi:10.1124/dmd.105.003616

Cited by 63 publications

(48 citation statements)

References 24 publications

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“…The pcDNA3.1(ϩ) plasmid containing human CYP2C9‫1ء‬ cDNA was constructed in our laboratory (Guo et al, 2005b). Site-directed mutagenesis to introduce the TTC3 GAC, TGG, and AAG transitions at position 298 to 300 (leading to F100D, F100W, and F100K substitution) was performed using pcDNA3.1(ϩ) plasmids carrying CYP2C9‫1ء‬ cDNA as the template for polymerase chain reaction amplification by Prime Star DNA polymerase (Takara Biotechnology).…”

Section: And Two Variants Transiently Expressed In Cos-7 Cellsmentioning

confidence: 99%

“…The pcDNA3.1(ϩ) plasmids containing the gene of human wild-type CYP2C9 and the three mutants were transiently transfected into COS-7 cells using Lipofectamine 2000 (Invitrogen). Expression was undertaken as described previously (Guo et al, 2005b), and the S9 fraction containing wild-type CYP2C9 and three variants was collected for assay or stored at Ϫ80°C. The quantity of expressed CYP2C9 protein was assayed by Western blotting as described previously (Guo et al, 2005b).…”

Section: Cyp2c9 Inhibition By Flavones and Flavonolsmentioning

confidence: 99%

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Mechanism of CYP2C9 Inhibition by Flavones and Flavonols

Wang²,

Zhou³

et al. 2008

Drug Metab Dispos

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ABSTRACT:This article describes an in vitro investigation of the inhibition of cytochrome P450 (P450) 2C9 by a series of flavonoids made up of flavones (flavone, 6-hydroxyflavone, 7-hydroxyflavone, chrysin, baicalein, apigenin, luteolin, scutellarein, and wogonin) and flavonols (galangin, fisetin, kaempferol, morin, and quercetin). With the exception of flavone, all flavonoids were shown to inhibit CYP2C9-mediated diclofenac 4-hydroxylation in the CYP2C9 RECO system, with K i value <2.2 M. In terms of the mechanism of inhibition, 6-hydroxyflavone was found to be a noncompetitive inhibitor of CYP2C9, whereas the other flavonoids were competitive inhibitors. Computer docking simulation and constructed mutants substituted at residue 100 of CYP2C9.1 indicate that the noncompetitive binding site of 6-hydroxyflavone lies beside Phe100, similar to the reported allosteric binding site of warfarin. The other flavonoids exert competitive inhibition through interaction with the substrate binding site of CYP2C9 accessed by flurbiprofen. These results suggest flavonoids can participate in interactions with drugs that act as substrates for CYP2C9 and provide a possible molecular basis for understanding cooperativity in human P450-mediated drug-drug interactions.Flavonoids are polyphenolic secondary metabolites that are widely distributed in higher plants and ingested by humans in their regular food (Kuhnau, 1976;Bravo, 1998). Flavones and flavonols are two major classes of flavonoids (Table 1). Flavonols are present in a variety of fruits and vegetables, whereas flavones are mainly found in cereals and herbs (Hertog et al., 1993;Bravo, 1998;Peterson and Dwyer, 1998). In the West, the estimated daily intake of both flavonols and flavones is in the range 20 to 50 mg per day (Cermak and Wolffram, 2006). However, given the growing demand for food supplements or herbal remedies containing flavonoids, and given that in some countries flavonoids are commonly used as therapeutic agents (2008 State Food and Drug Administration RPC, http://app1.sfda.gov. cn/datasearch/face3/dir.html), it is likely that some individuals are exposed to relatively high levels of flavonoids. This points to a need for more information on the safety and potential toxicity of flavonoids.In the early 1980s, several studies reported the effects of flavonoids on the activity of hepatic cytochrome P450 (P450) enzymes (Buening et al., 1981;Lasker et al., 1982). Since then, the ability of flavonoids to inhibit isoforms of CYP450, particularly CYP1A1 and CYP1A2, has been extensively confirmed (Cermak and Wolffram, 2006). Several clinical studies have reported that some flavonoids have the capacity to alter drug metabolism in vivo (Peng et al., 2003;Rajnarayana et al., 2003;Choi et al., 2004). However, for CYP2C9, which ranks among the most important drug-metabolizing enzymes in humans and hydroxylates 10 to 20% of commonly prescribed drugs (Kirchheiner and Brockmöller, 2005), only two flavones, luteolin and baicalein, and one flavonol, quercetin, have been found to ...

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Section: And Two Variants Transiently Expressed In Cos-7 Cellsmentioning

confidence: 99%

Section: Cyp2c9 Inhibition By Flavones and Flavonolsmentioning

confidence: 99%

Mechanism of CYP2C9 Inhibition by Flavones and Flavonols

Wang²,

Zhou³

et al. 2008

Drug Metab Dispos

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140

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“…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, 2001;Higashi et al, 2002).…”

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confidence: 99%

Differential Genotype Dependent Inhibition of CYP2C9 in Humans

Kumar

Brundage²,

Oetting³

et al. 2008

Drug Metab Dispos

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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., ...

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“…7 Additionally, CYP2C9*2 and CYP2C9*3 alleles reduce the clearance of warfarin and increase the risk of bleeding 15 and CYP2C9*13 Multidrug resistance associated protein 1 allele is associated with reduced metabolism of lornoxicam. 16 Similarly, CYP2C8 plays a role in the disposition of therapeutic drugs. 17 The intestinal epithelium and liver contain the most abundant member of the CYP family namely CYP3A and these enzymes are responsible for the metabolism of more than half of the therapeutic drugs.…”

Section: Drug Metabolizing Enzymesmentioning

confidence: 99%