Strongly increased exposure of meloxicam in CYP2C9*3/*3 individuals

Lee, Hye-In; Bae, Jung‐Woo; Choi, Chang‐Ik; Lee, Yun-Jeong; Byeon, J.Y.; Jang, Choon‐Gon; Lee, Seok‐Yong

doi:10.1097/fpc.0000000000000025

Cited by 23 publications

(19 citation statements)

References 10 publications

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“…A recent study supported the previous finding that individuals carrying CYP2C9*3/*3 exhibited a nine-fold lower apparent oral clearance of meloxicam, suggesting that CYP2C9*3/*3 individuals may be at a higher risk for adverse effects during long-term treatment with standard dose of meloxicam [86].…”

Section: Clinical Impact Of Cyp2c9 Genetic Variation On Drug Responsessupporting

confidence: 81%

Molecular functionality of CYP2C9 polymorphisms and their influence on drug therapy

Jarrar¹,

Lee²

2014

Drug Metabolism and Drug Interactions

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CYP2C9 metabolizes approximately 20% of clinically used drugs, including the narrow therapeutic window drugs warfarin and phenytoin. More than 16,000 variants have been reported in the National Center for Biotechnology Information CYP2C9 database, as well as 58 alleles in the official P450 Nomenclature Committee website. Two single nucleotide polymorphisms represented by the CYP2C9*2 and CYP2C9*3 alleles have been studied extensively. However, in addition to these two alleles, other genetic factors and an individual's biological characteristics contribute to the overall drug phenotype. A major bottleneck for CYP2C9 pharmacogenomics in clinical field applications is the lack of knowledge regarding the numerous genetic polymorphisms and their molecular functionalities. An unmet gap exists between the ever-growing number of genetic variants and their molecular mechanisms. In the present review, functional changes of all known CYP2C9 protein coding alleles were predicted using in silico analyses and compared with the in vitro and in vivo data. We also summarize functional information from recently reported CYP2C9 variants. Regarding the previously known CYP2C9 variants, we provide an update on the functional information obtained from in vitro and in vitro data.

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Section: Clinical Impact Of Cyp2c9 Genetic Variation On Drug Responsessupporting

confidence: 81%

Molecular functionality of CYP2C9 polymorphisms and their influence on drug therapy

Jarrar¹,

Lee²

2014

Drug Metabolism and Drug Interactions

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“…This proportional effect model has been used in several population PK analyses, including those for dextromethorphan, tolbutamide, and warfarin . However, the present calculated CL value of 0.0782 L/h in subjects with CYP2C9*3/*3 is greater than the meloxicam oral clearance of 0.043 ± 0.004 L/h, which was calculated using a noncompartmental analysis of Korean subjects (mean ± SD; n = 3) with the CYP2C9*3/*3 genotype, further indicating a comparatively large impact of the CYP2C9*3/*3 genotype. Thus, further studies are necessary to investigate the PK of rare allele combinations.…”

Section: Discussionmentioning

confidence: 60%

Pharmacokinetics and Pharmacodynamics of Meloxicam in East Asian Populations: The Role of Ethnicity on Drug Response

Aoyama

Ishida

Kaneko

et al. 2017

CPT Pharmacom & Syst Pharma

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We aimed to reanalyze the differences in the pharmacokinetics (PKs) of meloxicam in East Asian populations based on a population approach using previously published data and to investigate the factors found in population PK analysis that affect the pharmacodynamics (PDs) of meloxicam. Population PK analysis was performed in 119 healthy male subjects (30 Japanese, 30 Chinese, 29 Korean, and 30 white) under strictly controlled trial conditions with regulated meals and a single lot of the drug. We found that CYP2C9 genotype and lean body mass were statistically significant predictors of clearance and volume of distribution, respectively. A statistical significant difference in the PK parameters between ethnic groups could not be identified. Simulations using PK/PD models showed that CYP2C9 genotype is the factor that affects the PDs of meloxicam. The genetic polymorphisms highlighted in this study would be beneficial for conducting clinical trials in East Asians with similar genetic backgrounds.

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“…of function variants CYP2C9*3 (Andersson et al, 2012;Prieto-Pérez et al, 2013;Lee et al, 2014) and CYP2C19*3 (Scott et al, 2011(Scott et al, , 2013 (Fig. 1A).…”

Section: Downloaded Frommentioning

confidence: 98%

Pharmacogenomic Next-Generation DNA Sequencing: Lessons from the Identification and Functional Characterization of Variants of Unknown Significance inCYP2C9andCYP2C19

Devarajan¹,

Moon²,

Ho³

et al. 2019

Drug Metab Dispos

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CYP2C9 and CYP2C19 are highly polymorphic pharmacogenes; however, clinically actionable genetic variability in drug metabolism due to these genes has been limited to a few common alleles. The identification and functional characterization of less-common open reading frame sequence variation might help to individualize therapy with drugs that are substrates for the enzymes encoded by these genes. The present study identified seven uncharacterized variants each in CYP2C9 and CYP2C19 using next-generation sequence data for 1013 subjects, and functionally characterized the encoded proteins. Constructs were created and transiently expressed in COS-1 cells for the assay of protein concentration and enzyme activities using fluorometric substrates and liquid chromatography-tandem mass spectrometry with tolbutamide (CYP2C9) and (S)-mephenytoin (CYP2C19) as prototypic substrates. The results were compared with the SIFT, Polyphen, and Provean functional prediction software programs. Cytochrome P450 oxidoreductase (CPR) activities were also determined. Positive correlations were observed between protein content and fluorometric enzyme activity for variants of CYP2C9 (P < 0.05) and CYP2C19 (P < 0.0005). However, CYP2C9 709G>C and CYP2C19 65A>G activities were much lower than predicted based on protein content. Substrate intrinsic clearance values for CYP2C9 218C>T, 343A>C, and CYP2C19 337G>A, 518C>T, 556C>T, and 557G>A were less than 25% of wild-type allozymes. CPR activity levels were similar for all variants. In summary, sequencing of CYP2C9 and CYP2C19 in 1013 subjects identified low-frequency variants that had not previously been functionally characterized. In silico predictions were not always consistent with functional assay results. These observations emphasize the need for high-throughput methods for pharmacogene variant mutagenesis and functional characterization.

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Strongly increased exposure of meloxicam in CYP2C93/3 individuals

Abstract: These results indicate that CYP2C93/3 individuals may be at a higher risk for concentration-dependent adverse effects during long-term treatment with standard doses of meloxicam.

Cited by 23 publications

References 10 publications

Molecular functionality of CYP2C9 polymorphisms and their influence on drug therapy

Molecular functionality of CYP2C9 polymorphisms and their influence on drug therapy

Pharmacokinetics and Pharmacodynamics of Meloxicam in East Asian Populations: The Role of Ethnicity on Drug Response

Pharmacogenomic Next-Generation DNA Sequencing: Lessons from the Identification and Functional Characterization of Variants of Unknown Significance inCYP2C9andCYP2C19

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Strongly increased exposure of meloxicam in CYP2C9*3/*3 individuals

Abstract: These results indicate that CYP2C9*3/*3 individuals may be at a higher risk for concentration-dependent adverse effects during long-term treatment with standard doses of meloxicam.

Cited by 23 publications

References 10 publications

Molecular functionality of CYP2C9 polymorphisms and their influence on drug therapy

Molecular functionality of CYP2C9 polymorphisms and their influence on drug therapy

Pharmacokinetics and Pharmacodynamics of Meloxicam in East Asian Populations: The Role of Ethnicity on Drug Response

Pharmacogenomic Next-Generation DNA Sequencing: Lessons from the Identification and Functional Characterization of Variants of Unknown Significance inCYP2C9andCYP2C19

Contact Info

Product

Resources

About

Strongly increased exposure of meloxicam in CYP2C93/3 individuals

Abstract: These results indicate that CYP2C93/3 individuals may be at a higher risk for concentration-dependent adverse effects during long-term treatment with standard doses of meloxicam.