Genetic polymorphisms of CYP2C19 influences the response to clopidogrel in ischemic heart disease patients in the South Indian Tamilian population

Subraja, Kumaresan; Dkhar, Steven Aibor; Priyadharsini, R; Ravindra, Byrappa Kempalalakshmamma; Shewade, Deepak Gopal; Satheesh, Santhosh; Sridhar, Magadi Gopalakrishna; Narayan, Shyam; Chandrasekaran, Adithan

doi:10.1007/s00228-012-1381-8

Cited by 25 publications

(18 citation statements)

References 23 publications

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“…The distribution of CYP3A5*1/*1 (AA), *1/*3 (AG) and *3/*3 (GG) genotypes were 15.2 %, 43.5 % and 41.3 % respectively [17]. The role of CYP2C19 genotypes on the clopidogrel metabolism has already been studied in our population in relation to clopidogrel response variability [18]. Hence, this study evaluates the impact of CYP3A5*3 on ADP induced platelet aggregation inhibition response in patients on treatment with 75 mg maintenance dose of clopidogrel.…”

Section: Introductionmentioning

confidence: 94%

Single nucleotide polymorphism of CYP3A5*3 contributes to clopidogrel resistance in coronary artery disease patients among Tamilian population

Priyadharsini

Shewade

Subraja³

et al. 2014

Mol Biol Rep

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Clopidogrel is an antiplatelet drug. It is used for the treatment as well as for the prophylaxis of coronary artery disease. Clopidogrel resistance is an emerging problem in clinical settings. The aim of the present study was to evaluate the effect of CYP3A5*3 genetic polymorphism on clopidogrel resistance. One hundred and forty-seven patients from outpatient Department of Cardiology on 75 mg/day of clopidogrel as maintenance dose were recruited from April 2010 to July 2011. All subjects gave written informed consent to participate in the study. DNA extraction was performed using phenol chloroform extraction procedure and genotyping by standard Taqman based RT-PCR method. Platelet aggregation was done at the end of 7th and 14th day by using chronolog lumi Aggregometer which is expressed as impedance in ohms. Impedance values of >5 ohms at the end of 6 min were considered as clopidogrel resistance. Subjects (N = 147) were analysed for CYP3A5*3 polymorphism, of which 49 (33%) were found to be clopidogrel resistant. Homomutants of CYP3A5*3 gene had 2.78 (0.97-7.98; p < 0.05) fold risk and heteromutants had 2.4 (0.93-6.46; p < 0.05) fold risk of developing clopidogrel resistance. Carriers of defective allele G of CYP3A5*3 had higher propensity to cause clopidogrel resistance with an odds ratio of 1.63. Variant alleles and genotypes of CYP3A5*3 polymorphism contributed significantly to clopidogrel resistance with a higher odds ratio. Thus, pharmacogenomics paves way for the emergence of stratified medicine in clopidogrel therapy and personalised pharmacotherapy in ischaemic heart disease.

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Section: Introductionmentioning

confidence: 94%

Single nucleotide polymorphism of CYP3A5*3 contributes to clopidogrel resistance in coronary artery disease patients among Tamilian population

Priyadharsini

Shewade

Subraja³

et al. 2014

Mol Biol Rep

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“…17,18 In our previous studies we have explained the metabolic profiling for proguanil oxidation by CYP2C19, CYP2C9 induction/inhibition by phenytoin and phenytoin toxicity. 19,20 In the present study the metabolic ratio was calculated and the patients were stratified based on the required daily dose of warfarin. We have observed that the high dose group showed higher metabolic ratio, this may demonstrate that the phenomenon of saturation kinetics (zero order kinetics) of warfarin when dose is increased.…”

Section: Discussionmentioning

confidence: 99%

Estimation of plasma levels of warfarin and 7-hydroxy warfarin by high performance liquid chromatography in patients receiving warfarin therapy

Kumar¹,

Shewade²,

Parasuraman³

et al. 2013

Journal of Young Pharmacists

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a b s t r a c tWarfarin is one of the most commonly prescribed oral anticoagulant for prevention of thromboembolic events. The effect of this drug is measured by monitoring prothrombin time expressed as International Normalized Ratio (INR). In some cases, however, the measurement of plasma concentration of warfarin was emphasized. In the present study, reversed phase high performance liquid chromatography (HPLC) was used to estimate the plasma drug levels. A total of 185 patients were enrolled in this study. Five milliliter of venous blood was collected using sodium EDTA tubes for pharmacokinetic analysis. Solid phase extraction was used to recover the warfarin and it's metabolite from plasma using isopropanol and potassium phosphate buffer (40:60) mobile phase. Warfarin, 7-hydroxy warfarin and carbamazepine (internal standard) were separated on a C18 column and had the retention time 3.6 min, 2.9 min and 5.9 min, respectively. The assay was linear in warfarin concentration ranges of 0.1e5 mg/ml. The extraction recovery was found to be x85%. The mean plasma concentrations of warfarin and 7-hydroxy warfarin were found to be 3.47 AE 1.87 (SD) mg/ml, 1.25 AE 0.81 (SD) mg/ml, respectively. Through the present study the plasma concentrations of warfarin, 7-hydroxy warfarin and their metabolic ratio was determined. The assay was sensitive to follow warfarin pharmacokinetics in a patient with warfarin therapy for 3 months and above.

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“…For example, Jang et al [72] estimated that carriers of one or more CYP2C19 LOF alleles had an increased risk of cardiovascular death (OR 2.18, 95% CI 1.37 to 3.47), MI (OR 1.42, 95% CI 1.12 to 1.81), and stent thrombosis (OR 2.41, 95% CI 1.76 to 3.30). These effects appear to be qualitatively consistent across ethnic populations [74-76]. By contrast, a recent meta-analysis by Holmes and coworkers [77] concluded that CYP2C19 LOF variants are not clinically significant contributors to clopidogrel response, citing issues with “treatment only” study designs and small study bias as the reasons for positive findings of other meta-analyses.…”

Section: Clopidogrelmentioning

confidence: 99%

Pharmacogenomics of Anti-platelet and Anti-coagulation Therapy

et al. 2013

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Arterial thrombosis is a major component of vascular disease, especially myocardial infarction (MI) and stroke. Current anti-thrombotic therapies such as warfarin and clopidogrel are effective in inhibiting cardiovascular events; however, there is great inter-individual variability in response to these medications. In recent years, it has been recognized that genetic factors play a significant role in drug response, and, subsequently, common variants in genes responsible for metabolism and drug action have been identified. These discoveries along with the new diagnostic targets and therapeutic strategies on the horizon hold promise for more effective individualized anti-coagulation and anti-platelet therapy.

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Genetic polymorphisms of CYP2C19 influences the response to clopidogrel in ischemic heart disease patients in the South Indian Tamilian population

Cited by 25 publications

References 23 publications

Single nucleotide polymorphism of CYP3A5*3 contributes to clopidogrel resistance in coronary artery disease patients among Tamilian population

Single nucleotide polymorphism of CYP3A5*3 contributes to clopidogrel resistance in coronary artery disease patients among Tamilian population

Estimation of plasma levels of warfarin and 7-hydroxy warfarin by high performance liquid chromatography in patients receiving warfarin therapy

Pharmacogenomics of Anti-platelet and Anti-coagulation Therapy

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