Influence of CYP2C9, VKORC1, and CYP4F2 polymorphisms on the pharmacodynamic parameters of warfarin: a cross-sectional study

Sridharan, Kannan; Banna, Rashed Al; Malalla, Zainab H.; Husain, Aysha; Sater, Mai S.; Jassim, Ghufran; Otoom, Sameer

doi:10.1007/s43440-021-00256-w

Cited by 12 publications

(6 citation statements)

References 18 publications

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“…Evaluation of CYP2C9, VKORC1, and CYP4F2 genetic polymorphisms before initiation of warfarin therapy may be useful to optimize the therapeutic effect of warfarin (Sridharan et al, 2021). Including the information on CYP4F2 Val433Met variants along with CYP2C9 and VKORC1 variant information to predict an appropriate warfarin dose improves the prediction of a stable warfarin dose (Danese et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Functional Characterization of 29 Cytochrome P450 4F2 Variants Identified in a Population of 8380 Japanese Subjects and Assessment of Arachidonic Acidω-Hydroxylation

Sato,

Hishinuma,

Yamazaki

et al. 2023

Drug Metab Dispos

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Cytochrome P450 4F2 (CYP4F2) is an enzyme that is involved in the metabolism of arachidonic acid (AA), vitamin E and K (VK), and xenobiotics including drugs. CYP4F2*3 polymorphism (rs2108622; c.1297G>A; p.Val433Met) has been associated with hypertension, ischemic stroke, and variation in the effectiveness of the anticoagulant drug warfarin. In this study, we characterized wild-type CYP4F2 and 28 CYP4F2 variants, including a Val433Met substitution, detected in 8,380 Japanese subjects. The CYP4F2 variants were heterologously expressed in 293FT cells to measure the concentrations of CYP4F2 variant holoenzymes using carbon monoxide-reduced difference spectroscopy, where the wild type and 18 holoenzyme variants showed a peak at 450 nm. Kinetic parameters (V max , S 50 , and CL int as V max /S 50 ) of AA ω-hydroxylation were determined for the wild type and 21 variants with enzyme activity.Compared to the wild type, two variants showed significantly decreased CL int values for AA ω-hydroxylation. The values for seven variants could not be determined because no enzymatic activity was detected at the highest substrate concentration used. Three-dimensional structural modeling was performed to determine the reason for reduced enzymatic activity of the CYP4F2 variants. Our findings contribute to a better understanding of CYP4F2 variant-associated diseases and possible future therapeutic strategies.

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Section: Discussionmentioning

confidence: 99%

Functional Characterization of 29 Cytochrome P450 4F2 Variants Identified in a Population of 8380 Japanese Subjects and Assessment of Arachidonic Acidω-Hydroxylation

Sato,

Hishinuma,

Yamazaki

et al. 2023

Drug Metab Dispos

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“…We also compared the mean geneticbased calculated daily doses, estimated by the Gage algorithm with an additional 30% dose reduction for each CYP2C9 *8 or *11 allele, 5 in the warfarin-responders and nonresponders. Additionally, we compared the percentage time in therapeutic range (TTR), calculated by the Rosendaal method, 43 as well as the warfarin sensitivity index (WSI), 44,45 defined as the average INR divided by the corresponding maintenance dose or maximum-tried dose, in the carriers and the noncarriers of warfarinsensitizing CYP2C9/VKORC1 genotypes. In addition, we investigated the WSI correlation with the genetic-based calculated dose requirements.…”

Section: Methodsmentioning

confidence: 99%

Warfarin‐Rifampin‐Gene (WARIF‐G) Interaction: A Retrospective, Genetic, Case–Control Study

Salem

El-Bardissy

Elshafei

et al. 2023

Clin Pharma and Therapeutics

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Warfarin is extensively metabolized by cytochrome P450 2C9 (CYP2C9). Concomitant use with the potent CYP2C9 inducer, rifampin, requires close monitoring and dosage adjustments. Although, in theory, warfarin dose increase should overcome this interaction, most reported cases over the last 50 years have not responded even to high warfarin doses, but some have responded to modest doses. To investigate the genetic polymorphisms' impact on this unexplained interpatient variability, we performed genotyping of CYP2C9, VKORC1, and CYP4F2 for warfarin and rifampin concomitant receivers from 2016 to 2022 at Hamad Medical Corporation, Doha, Qatar. We identified and included 36 patients: 22 responders and 14 nonresponders. Warfarin-responders were significantly more likely to have one or more warfarin-sensitizing CYP2C9/VKORC1 alleles than nonresponders (odds ratio = 23.2, 95% confidence interval = 3.2-195.6; P = 0.0001). The mean genetic-based pre-interaction calculated dose was significantly lower for responders than for nonresponders (P < 0.001); and was negatively correlated with warfarin sensitivity index (WSI) (r = −0.58; P = 0.0002). The median percentage time in therapeutic range and mean WSI were significantly higher in the warfarin-sensitizing CYP2C9/VKORC1 alleles carriers than noncarriers (P = 0.017 and 0.0004, respectively). Whereas the warfarin-sensitizing CYP2C9/VKORC1 genotypes were associated with modest onrifampin warfarin dose requirements, the noncarriers would have required more than double these doses to respond. Warfarin-sensitizing CYP2C9/VKORC1 genotypes and low genetic-based warfarin calculated doses were associated with higher warfarin sensitivity and better anticoagulation quality in patients receiving rifampin concomitantly.

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“…The genomic DNA was extracted from the peripheral blood leukocytes using a QIAamp ® DNA blood mini kit (Qiagen). The concentrations of DNA were measured using a Nanodrop spectrophotometer [ 17 ]. SNPs were genotyped using the allelic discrimination method on a StepOne Plus ® real-time PCR system (Applied Biosystems; Foster City, CA, USA) according to the manufacturer’s instructions using commercially available TaqMan ® assays.…”

Section: Methodsmentioning

confidence: 99%

Evaluation of Pharmacogenetics of Drug-Metabolizing Enzymes and Drug Efflux Transporter in Renal Transplants Receiving Immunosuppressants

Sridharan

Shah

Jasim

et al. 2022

JPM

Self Cite

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Cytochrome P450 (CYP) enzymes, such as CYP3A4, and CYP3A5, P450 oxidoreductase (POR), peroxisome proliferator activated receptor alpha (PPAR-alpha), and drug transporter (ABCB1) were observed to influence concentrations of immunosuppressants (cyclosporine, everolimus, sirolimus, and tacrolimus) and outcomes in renal transplants. We carried out the present study to evaluate the prevalence and impact of these single nucleotide polymorphisms (SNPs) in adult renal transplants. SNPs were evaluated using commercial TaqMan® assays. Serum drug concentrations were estimated using immunoassays. One hundred and forty-six patients were recruited. SNPs in CYP3A5*3 were significantly associated with greater dose-adjusted cyclosporine and tacrolimus concentrations. SNPs in POR*28 were observed with significantly lower dose-adjusted concentrations, particularly with cyclosporine and tacrolimus. ABCB1 homozygous polymorphisms were observed with significantly lower time spent in the therapeutic range with cyclosporine and everolimus/sirolimus. Cyclosporine was observed in a significantly greater proportion of patients with elevated GGT, and SNPs in PPAR-alpha were significantly associated with an increased risk of this adverse event. Hypertriglyceridemia with everolimus was significantly associated with POR*28 polymorphisms. There is a need to validate the influence of these SNPs in a prospective study and develop an algorithm predicting the achievement of target concentrations.

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Influence of CYP2C9, VKORC1, and CYP4F2 polymorphisms on the pharmacodynamic parameters of warfarin: a cross-sectional study

Cited by 12 publications

References 18 publications

Functional Characterization of 29 Cytochrome P450 4F2 Variants Identified in a Population of 8380 Japanese Subjects and Assessment of Arachidonic Acidω-Hydroxylation

Functional Characterization of 29 Cytochrome P450 4F2 Variants Identified in a Population of 8380 Japanese Subjects and Assessment of Arachidonic Acidω-Hydroxylation

Warfarin‐Rifampin‐Gene (WARIF‐G) Interaction: A Retrospective, Genetic, Case–Control Study

Evaluation of Pharmacogenetics of Drug-Metabolizing Enzymes and Drug Efflux Transporter in Renal Transplants Receiving Immunosuppressants

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