Reduced-function Alleles Research Articles

Non-Carriers of Reduced-Function CYP2C19 Alleles are Most Susceptible to Impairment of the Anti-Platelet Effect of Clopidogrel by Proton-Pump Inhibitors: A Pilot Study.

The phenomenon of CYP2C19 polymorphism affects the metabolism of both clopidogrel and proton-pump inhibitors (PPI). However, concomitant use of both drugs may reduce the desired therapeutic effects. In this study, we evaluated whether individuals with different numbers of reduced-function CYP2C19 alleles were equally affected and whether PPIs with different dependencies on CYP2C19 metabolism were equally involved. Thirty healthy volunteers were recruited to a six-week regimen of clopidogrel. Three PPIs with different metabolic dependencies on CYP2C19 were included and separately administered in this order. Each PPI was given for a week, followed by a one-week washout period before the intervention of the next PPI. The anti-platelet effect was examined by Thromboelastography Platelet Mapping(TM) (TEG®) and vasodilator-stimulated phosphoprotein (VASP) assays. Both TEG® and VASP tests showed the same general qualitative trend, but TEG® detected a statistically significant fluctuation of platelet aggregation in response to different drug interventions. The TEG® results also demonstrated that non-carriers experienced the most significant impairment of anti-platelet effect of clopidogrel after concomitant use of PPIs. This impairment was closely related to the metabolic dependence on CYP2C19 of PPI. Our study indicated that non-carriers of reduced-function CYP2C19 alleles are most susceptible to impairment of the anti-platelet effect of clopidogrel after concomitant PPI use. Individual subjects are not equally affected, and PPIs are not equally involved. However, large-scale randomized clinical trials are needed to evaluate the clinical outcome. Clopidogrel • CYP2C19 polymorphism • Platelet aggregation • Proton pump inhibitors • TEG • VASP.

Hyper-Response to Clopidogrel in Japanese Patients Undergoing Transcatheter Aortic Valve Implantation.

Dual antiplatelet therapy is empirically recommended following transcatheter aortic valve implantation (TAVI). The aims of the present study were to analyze the effect of clopidogrel on platelet function and to determine the relative contribution of each CYP2C19 loss-of-function genotype undergoing TAVI.Thirty-two patients undergoing TAVI and with clopidogrel treatment were studied. All patients were treated with an Edwards SapienXT valve. Platelet reactivity was measured by the VerifyNow P2Y12 point-of-care assay at 7 days and 30 days after the procedure and a cutoff value of 95 PRU was used to identify a hyper-response of platelet reactivity. The Spartan RX(TM) sample-to-result point-of-care DNA testing system was used to identify CYP2C19 loss-of-function genotypes. Hyper-response of platelet reactivity was identified in 11 (34.3%) patients, although 24 (80%) were carriers of at least one CYP2C19 reduced-function allele. The PRU values did not change significantly from 7 days to 30 days after TAVI (136.7 ± 73.4 versus 150.4 ± 83.2, P = 0.13). The incidences of life-threatening bleeding, minor bleeding, and transfusion were significantly higher among the hyper-response of platelet reactivity group (27.3% versus 0%, P = 0.03, 36.4% versus 4.8%, P = 0.04, 81.8% versus 42.9%, P = 0.04, respectively).A hyper-response to clopidogrel was observed in one-third of patients undergoing TAVI and was related to bleeding events, even though 80% of the patients were carriers of the CYP2C19 reduced-function allele.

Organic cation transporter 1 variants and gastrointestinal side effects of metformin in patients with Type 2 diabetes.

AimsMetformin is the most widely used oral anti‐diabetes agent and has considerable benefits over other therapies, yet 20–30% of people develop gastrointestinal side effects, and 5% are unable to tolerate metformin due to the severity of these side effects. The mechanism for gastrointestinal side effects and their considerable inter‐individual variability is unclear. We have recently shown the association between organic cation transporter 1 (OCT1) variants and severe intolerance to metformin in people with Type 2 diabetes. The aim of this study was to explore the association of OCT1 reduced‐function polymorphisms with common metformin‐induced gastrointestinal side effects in Type 2 diabetes.MethodsThis prospective observational cohort study included 92 patients with newly diagnosed Type 2 diabetes, incident users of metformin. Patients were genotyped for two common loss‐of‐function variants in the OCT1 gene (SLC22A1): R61C (rs12208357) and M420del (rs72552763). The association of OCT1 reduced‐function alleles with gastrointestinal side effects was analysed using logistic regression.ResultsForty‐three patients (47%) experienced gastrointestinal adverse effects in the first 6 months of metformin treatment. Interestingly, the number of OCT1 reduced‐function alleles was significantly associated with over two‐fold higher odds of the common metformin‐induced gastrointestinal side effects (odds ratio = 2.31, 95% confidence interval 1.07–5.01, P = 0.034).ConclusionsIn conclusion, we showed for the first time the association between OCT1 variants and common metformin‐induced gastrointestinal side effects. These results confirm recent findings related to the role of OCT1 in severe metformin intolerance, and suggest that high inter‐individual variability in mild/moderate and severe gastrointestinal intolerance share a common underlying mechanism. These data could contribute to more personalized and safer metformin treatment.

Endogenous glucose production increases in response to metformin treatment in the glycogen-depleted state in humans: a randomised trial.

Metformin is believed to reduce glucose levels primarily by inhibiting hepatic glucose production. Recent data indicate that metformin antagonises glucagon-dependent glucose output, suggesting that compensatory mechanisms protect against hypoglycaemia. Here, we examined the effect of metformin on glucose metabolism in humans after a glycogen-depleting fast and the role of reduced-function alleles in OCT1 (also known as SLC22A1). In a randomised, crossover trial, healthy individuals with or without reduced-function alleles in OCT1 were fasted for 42 h twice, either with or without prior treatment with 1 g metformin twice daily. Participants were recruited from the Pharmacogenomics Biobank of the University of Southern Denmark. Treatment allocation was generated by the Good Clinical Practice Unit, Odense University Hospital, Denmark. Variables of whole-body glucose metabolism were assessed using [3-(3)H]glucose, indirect calorimetry and measurement of substrates and counter-regulatory hormones. The primary outcome was endogenous glucose production (EGP). Thirty-seven individuals were randomised. Thirty-four completed the study (12 had none, 13 had one and nine had two reduced-function alleles in OCT1). Three were excluded from the analysis because of early dropout. Metformin significantly stimulated glucose disposal rates and non-oxidative glucose metabolism with no effect on glucose oxidation. This increase in glucose utilisation was explained by a concomitant increase in glycolytic flux and accompanied by increased EGP, most likely mediated by increased plasma lactate, glucagon and cortisol levels. There was no effect of reduced-function OCT1 alleles on any of these measures. All individuals completed the glycogen-depleting fast without hypoglycaemia. Metformin stimulates glycolytic glucose utilisation and lactate production in the glycogen-depleted state. This may trigger a rise in glucose counter-regulatory hormones and subsequently an increase in EGP, which protects against hypoglycaemia. ClinicalTrials.gov NCT01400191 FUNDING: Danish Research Council for Health and Disease (0602-02695B) and Odense University Hospital Free Research Fund, 2012.

Steady-state pharmacokinetics of metformin is independent of the OCT1 genotype in healthy volunteers

The aim of the study was to determine the steady-state pharmacokinetics of metformin in healthy volunteers with different numbers of reduced-function alleles in the organic cation transporter 1 gene (OCT1). The study was conducted as part of a randomized cross-over trial. Thirty-four healthy volunteers with known OCT1 genotypes (12 with two wild-type alleles, 13 with one and 9 with two reduced-function alleles) were included. In one of the study periods, they were titrated to steady-state with 1 g metformin twice daily. Neither AUC(0-12), C(max) nor Cl(renal) were statistically significantly affected by the number of reduced-function alleles (0, 1 or 2) in OCT1: (AUC(0-12): 0, 1, 2: 14, 13 and 14 h ng/L (P = 0.61)); (C(max): 0, 1, 2: 2192, 1934 and 2233 ng/mL, (P = 0.26)) and (Cl(renal): 0, 1, 2: 31, 28 and 30 L/h (P = 0.57)) CONCLUSIONS: In a cohort of healthy volunteers, we found no impact of different OCT1 genotypes on metformin steady-state pharmacokinetics.

HM4 - How Much Evidence Do We Need Before Implementing Pharmacogenomic Testing In The Clinic?

Consensus on the evidence required to recommend clinical pharmacogenomic testing is unclear. A formal assessment of pharmacogenomic evidence levels in relation to other clinical interventions, such as avoiding drug-drug interactions (DDI), may be helpful for policymakers. The objective of this study was to quantitatively compare the evidence levels of two contested drug-attenuating interactions with clopidogrel antiplatelet therapy, and assess the value of obtaining additional evidence to inform clinical practice guidelines. We developed analogous value of information (VOI) decision models for: (1) avoidance of proton pump inhibitors (PPIs) in clopidogrel patients, and (2) pharmacogenomic-guided antiplatelet selection, both versus no intervention. Interaction-specific parameters and model structures were the only dissimilarities. We calculated the expected value of obtaining perfect information (EVPI) per patient, and the expected population value of obtaining additional information through future studies (EVSI). Current evidence for interaction-1 was slightly less uncertain (a 20% probability of making a non-optimal recommendation) than for interaction-2 (23%). The relative risk for cardiovascular death (conferred by concomitant PPI use in interaction-1, and reduced-function CYP2C19 alleles in interaction-2) was the greatest source of uncertainty in both models. The expected value of perfect information for interaction-1 was $139 per patient, compared to $242 per patient for interaction-2. In simulated 10,000-patient clinical trials, the expected population value of future research for interaction-1 was $2 million, versus $110 million for interaction-2. The evidence levels for clopidogrel DDI and pharmacogenomic effects appear to be fairly similar. However, the value of conducting future research on clopidogrel pharmacogenomics is higher because of greater uncertainty about the impact of pharmacogenomic testing on cardiovascular mortality. Our findings imply that evidence-based clinical guidelines for DDI and pharmacogenomic effects should be generally similar with regard to direction and strength of recommendation. This contrasts to some degree with current guidelines and drug labeling.

CYP2C19 polymorphism and clinical outcomes among patients of different races treated with clopidogrel: A systematic review and meta-analysis

Several studies have investigated the association between CYP2C19 polymorphism and clinical outcomes of patients treated with clopidogrel, but few have noticed the difference in association between Westerners and Asians. We searched MEDLINE, EMBASE and Cochrane Library database and conducted a systematic review and meta-analysis. Thirty-six studies involving 44 655 patients with coronary artery disease (CAD) treated with clopidogrel were included, of which more than 68% had undergone percutaneous coronary intervention (PCI). The primary outcome of our interest was the recurrence of major adverse cardiovascular events (MACE) in those CAD patients. Firstly, we found that the distribution of reduced-function CYP2C19 allele varied between Westerners and Asians. Among Asians, 1 and 2 reduced-function CYP2C19 mutant allele carriers accounted for 42.5% and 10%, respectively. While among Westerners, 1 and 2 reduced-function CYP2C19 mutant allele carriers accounted for 25.5% and 2.4%, respectively. Secondly, the impact of CYP2C19 polymorphism on clinical outcomes of patients treated with clopidogrel varied with races. Among Asians, only 2 reduced-function CYP2C19 mutant allele carriers had the reduced effect of clopidogrel. And the reduced effect was significant only after the 30th day of treatment. While among Westerners, both 1 and 2 reduced-function CYP2C19 allele carriers had the reduced effect, and it mainly occurred within the first 30 days. Thirdly, the safety of clopidogrel was almost the same among races. Reduced-function allele non-carriers had higher risk for total bleeding but did not have higher risk for major bleeding. It is suggested that CYP2C19 polymorphism affects the efficacy of clopidogrel differently among Westerners and Asians.

Optimal cutoff value of P2Y12 reaction units to prevent major adverse cardiovascular events in the acute periprocedural period: Post-hoc analysis of the randomized PRASFIT-ACS study

BackgroundFew studies have examined the effects of on-treatment platelet reactivity on the risk of major adverse cardiovascular events (MACE). We aimed to determine the optimal cutoff value of P2Y12 reaction units (PRUs) to prevent MACE occurring within 3days after percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS). MethodsWe performed post-hoc analyses of 1363 patients enrolled in PRASFIT-ACS, which compared the effects of a prasugrel regimen adjusted for Japanese patients (loading dose/maintenance dose: 20mg/3.75mg) with those of clopidogrel (300mg/75mg) on MACE and bleeding events for 24–48weeks after PCI in ACS patients. PRU was serially measured using the VerifyNow® P2Y12 assay and we assessed the relationship between PRU and MACE. ResultsReceiver operating characteristic curve analysis showed that PRU ≤262 at 5–12h after ADP receptor antagonist loading was the optimal cutoff value for preventing MACE at up to 3days after PCI. The incidences of MACE were 5.2% and 10.8% in patients with PRU ≤262 or >262, respectively (odds ratio 0.50, 95% confidence interval 0.25–0.99, p<0.01). Significantly more prasugrel-treated patients had lower on-treatment platelet reactivity (defined as PRU ≤262) compared with clopidogrel-treated patients (79.9% vs. 30.4%, p<0.0001). Similar differences were observed between the prasugrel and clopidogrel groups for patients with normal or reduced-function CYP2C19 alleles. ConclusionsThe optimal PRU cutoff value for preventing MACE was 262 in Japanese ACS patients. Prasugrel rapidly reduced PRU with a large proportion of patients having low on-treatment platelet reactivity.

Association of Organic Cation Transporter 1 With Intolerance to Metformin in Type 2 Diabetes: A GoDARTS Study.

Metformin is the most widely prescribed medication for the treatment of type 2 diabetes (T2D). However, gastrointestinal (GI) side effects develop in ~25% of patients treated with metformin, leading to the discontinuation of therapy in ~5% of cases. We hypothesized that reduced transport of metformin via organic cation transporter 1 (OCT1) could increase metformin concentration in the intestine, leading to increased risk of severe GI side effects and drug discontinuation. We compared the phenotype, carriage of reduced-function OCT1 variants, and concomitant prescribing of drugs known to inhibit OCT1 transport in 251 intolerant and 1,915 fully metformin-tolerant T2D patients. We showed that women and older people were more likely to be intolerant to metformin. Concomitant use of medications, known to inhibit OCT1 activity, was associated with intolerance (odds ratio [OR] 1.63 [95% CI 1.22-2.17], P = 0.001) as was carriage of two reduced-function OCT1 alleles compared with carriage of one or no deficient allele (OR 2.41 [95% CI 1.48-3.93], P < 0.001). Intolerance was over four times more likely to develop (OR 4.13 [95% CI 2.09-8.16], P < 0.001) in individuals with two reduced-function OCT1 alleles who were treated with OCT1 inhibitors. Our results suggest that reduced OCT1 transport is an important determinant of metformin intolerance.

Genetic variation in key genes associated with statin therapy in the Azores Islands (Portugal) healthy population

Background: Inter-individual variation in response to statins (efficacy and toxicity) has been described and may be due to polymorphisms implicated in drug pharmacokinetics or pharmacodynamics.Aim: This study investigates clinically relevant pharmacogenes underlying statin response in 170 healthy Azoreans.Methods: Eight SNPs in candidate genes—HMGCR (rs3846662, rs17238540, rs17244841), CETP (rs708272), APOE (rs7412, rs429358) and SLCO1B1 (rs2306283, rs4149056)—were genotyped.Results: The allele frequencies were similar to those reported for European derived populations, excepting SLCO1B1 c.388A>G (rs2306283), which has a significant difference when compared with the HapMap CEU population (p = 1 × 10−8). The results of statin efficacy showed that 9.1% of Azoreans are APOE4 carriers. This allele has been associated with lower LDLc reduction from statin therapy and also higher LDLc levels at baseline. Regarding SLCO1B1, associated with statin toxicity, 1.8% of individuals have two reduced-function alleles (c.521CC).Conclusion: The results contribute to overcome the lack of knowledge regarding the frequency of pharmacogenetic SNPs and their corresponding haplotypes in targeted populations, such as Azores islands. Moreover, the present work constitutes an initial step to implementing pharmacogenomics in clinical practice where physicians could use a patient’s genetic make-up to optimize statin therapy, regarding efficiency and myopathy risk.

Lack of association between peri-procedural myocardial damage and CYP2C19 gene variant in elective percutaneous coronary intervention.

Peri-procedural myocardial damage (MD) is associated with increased risk of major in-hospital complications and adverse clinical events. The aim of this study was to evaluate the effects of on-clopidogrel platelet aggregation and CYP2C19-reduced-function gene variants on elective percutaneous coronary intervention (PCI)-related MD. We measured changes in serum high-sensitive troponin T (hs-TnT) levels, CYP2C19 genotype, and on-clopidogrel platelet aggregation (PA) using VerifyNow(®) P2Y12 system in 91 patients who received stent implantation (stent group). The control group comprised 30 patients who did not receive PCI. Blood samples were obtained before and 24h after PCI or coronary angiography (CAG). Patients of the stent group were divided into high and low MD groups based on the median value of hs-TnT level at 24h after PCI. Serum hs-TnT levels were significantly higher 24h after PCI (86.8±121.5pg/ml) compared with before PCI (9.4±5.3, p<0.001), whereas the levels were identical before and 24h after CAG in the control group. Simple logistic regression analysis demonstrated that MD correlated with age (p=0.014), estimated GFR (p=0.003), hemoglobin A1c (p=0.015), baseline serum hs-TnT (p=0.049), and stent length (p<0.001). Multiple logistic regression analysis identified old age, high hemoglobin A1c level, and long stent, but not CYP2C19 reduced-function allele or high on-clopidogrel PA, as independent predictors of elective PCI-related MD. The present study demonstrated no significant relation between peri-procedural MD and high on-clopidgrel PA associated with CYP2C19 reduced-function allele in patients undergoing elective PCI.

Association analysis of UGT1A genotype and haplotype with SN-38 glucuronidation in human livers.

7-ethyl-10-hydroxycamptothecin (SN-38), the active metabolite of irinotecan, is mainly eliminated hepatically through glucuronidation by UGT1A1 and UGT1A9 enzymes. This study comprehensively investigates the effects of UGT1A1 and UGT1A9 genetic polymorphism on SN-38 glucuronidation activity. Genetic polymorphisms and combinational haplotypes of UGT1A1 and UGT1A9, SN-38 glucuronidation activities, and protein levels of UGT1A1 and UGT1A9 were determined using a set of over 45 Chinese livers. UGT1A1 reduced function variants UGT1A1*6, *28, *60 and *1B exhibited additive effect. The number of UGT1A1 reduced function alleles was associated with decreased SN-38G formation rates and UGT1A protein levels. UGT1A9 I399C>T and UGT1A9*1b, which were highly linked, were associated with increased SN-38 glucuronidation activity and UGT1A protein levels. However, further analysis based on UGT1A9-1A1 haplotypes confirmed that their increased effect was partly due to their close linkage with UGT1A1 reduced function alleles. UGT1A1 genetic polymorphisms have a more important function in human liver SN-38 glucuronidation activity than UGT1A9. Original submitted 7 November 2013; Revision submitted 30 January 2014.

Serum Concentrations of Risperidone and Aripiprazole in Subgroups Encoding CYP2D6 Intermediate Metabolizer Phenotype

Cytochrome P450 2D6 intermediate metabolizer phenotype (CYP2D6 IM) comprises various genotype subgroups. The aim of this study was to evaluate serum concentrations of the CYP2D6 substrates risperidone and aripiprazole in psychiatric patients with various CYP2D6 genotypes encoding IM phenotype. The study was based on therapeutic drug monitoring data from CYP2D6-genotyped patients (mainly of white origin) treated with orally administered risperidone (n = 190) or aripiprazole (n = 266). Patients were divided into 3 genotype subgroups encoding IM phenotype: (1) heterozygous carriers of fully functional and nonfunctional variant alleles (*1/def), (2) homozygous carriers of reduced-function variant alleles (red/red), and (3) heterozygous carriers of reduced-function and nonfunctional variant alleles (def/red). Dose-adjusted serum concentrations of risperidone and aripiprazole were compared between the genotype subgroups using *1/def, the most frequent CYP2D6 genotype among these subgroups, as the reference group. Median serum concentrations were 4.5- and 1.6-fold higher in the def/red genotype than the *1/def genotype for risperidone and aripiprazole, respectively (P < 0.01 for both). Correspondingly, the serum concentrations were 3.4- and 1.8-fold higher in the red/red subgroup compared with the reference group (P < 0.05 for both). In conclusion, this study revealed substantial variability in serum concentrations of risperidone and aripiprazole between CYP2D6 genotypes associated with IM phenotype. A considerable phenotypical difference was observed between patients carrying 1 and 2 variant alleles.

Impact of CYP2C19 Polymorphism on Platelet Function Tests and Coagulation and Inflammatory Biomarkers in Patients Undergoing Percutaneous Coronary Intervention

Carriers of the reduced-function CYP2C19 allele receiving dual antiplatelet therapy (DAPT) with aspirin and clopidogrel exhibit diminished platelet inhibition and an increased risk of events. The purpose of this study was to investigate the effects of CYP2C19 gene variants on platelet function tests and coagulation and inflammatory biomarkers in patients undergoing elective percutaneous coronary intervention (PCI). This prospective, observational, multicenter study enrolled 104 consecutive Japanese patients undergoing elective PCI. We examined the CYP2C19 genotype, platelet function tests, the levels of coagulation and inflammatory biomarkers and the serum levels of high-sensitivity troponin T (hs-TnT) before, immediately after and one, two and 28 days after PCI. A total of 68 (65%) of the 104 enrolled patients were carriers of the CYP2C19 reducedfunction allele. On-clopidogrel platelet aggregation (PA), measured using light transmittance aggregometry and the VerifyNow(®) P2Y12 system, and the platelet reactivity index (PRI) were significantly higher at all time points in the carriers than in the noncarriers (p＜0.05), whereas there were no differences in the levels of the coagulation and inflammatory biomarkers or serum hs-TnT. Simple and multiple logistic regression analyses identified on-clopidogrel PA and PRI as being significant predictors of carriers of the CYP2C19 reduced-function allele. The present study suggests that platelet function tests, but not coagulation, inflammatory or cardiac biomarkers, are useful for identifying carriers of CYP2C19 reduced-function gene variants and monitoring the efficacy of DAPT in patients undergoing elective PCI.

Metabolism and Transport of Tamoxifen in Relation to its Effectiveness: New Perspectives on an Ongoing Controversy

Tamoxifen reduces the rate of breast cancer recurrence by approximately a half. Tamoxifen is metabolized to more active metabolites by enzymes encoded by polymorphic genes, including cytochrome P450 2D6 (CYP2D6). Tamoxifen is a substrate for ATP-binding cassette transporter proteins. We review tamoxifen's clinical pharmacology and use meta-analyses to evaluate the clinical epidemiology studies conducted to date on the association between CYP2D6 inhibition and tamoxifen effectiveness. Our findings indicate that the effect of both drug-induced and/or gene-induced inhibition of CYP2D6 activity is likely to be null or small, or at most moderate in subjects carrying two reduced function alleles. Future research should examine the effect of polymorphisms in genes encoding enzymes in tamoxifen's complete metabolic pathway, should comprehensively evaluate other biomarkers that affect tamoxifen effectiveness, such as the transport enzymes, and focus on subgroups of patients, such as premenopausal breast cancer patients, for whom tamoxifen is the only guideline endocrine therapy.

Impact of CYP2C19 Genetic Testing on Provider Prescribing Patterns for Antiplatelet Therapy After Acute Coronary Syndromes and Percutaneous Coronary Intervention

Patients treated with clopidogrel who have ≥1 loss of function alleles for CYP2C19 have an increased risk for adverse cardiovascular events. In 2010, the US Food and Drug Administration issued a boxed warning cautioning against the use of clopidogrel in such patients. We sought to assess the impact of CYP2C19 genetic testing on prescribing patterns for antiplatelet therapy among patients with acute coronary syndrome or percutaneous coronary intervention. Patients with recent acute coronary syndrome or percutaneous coronary intervention prescribed clopidogrel were offered CYP2C19 testing. Genotype and phenotype results were provided to patients and their physicians, but no specific treatment recommendations were suggested. Patients were categorized based on their genotype (carriers versus noncarriers) and phenotype (extensive, intermediate, and poor metabolizers). The primary outcome was intensification in antiplatelet therapy defined as either dose escalation of clopidogrel or replacement of clopidogrel with prasugrel. Between July 2010 and April 2012, 6032 patients were identified, and 499 (8.3%) underwent CYP2C19 genotyping, of whom 146 (30%) were found to have ≥1 reduced function allele, including 15 (3%) with 2 reduced function alleles. Although reduced function allele carriers were significantly more likely than noncarriers to have an intensification of their antiplatelet therapy, only 20% of poor metabolizers of clopidogrel had their antiplatelet therapy intensified. Providers were significantly more likely to intensify antiplatelet therapy in CYP2C19 allele carriers, but only 20% of poor metabolizers of clopidogrel had an escalation in the dose of clopidogrel or were switched to prasugrel. These prescribing patterns likely reflect the unclear impact and evolving evidence for clopidogrel pharmacogenomics.

CYP2D6 genotype and tamoxifen response for breast cancer: a systematic review and meta-analysis.

ObjectiveTo evaluate evidence on the association between CYP2D6 genotype and tamoxifen response through.DesignSystematic review and meta-analysis of prospective, cross-sectional and case-control studies published to 2012. For each study, relative risks and 95% confidence intervals were extracted and pooled with a fixed and random effects model. Heterogeneity, publication bias, subgroup, and meta-regression analyses were performed.Data SourcesPubMed (inception-2012) and EMBASE (inception-2012).Eligibility Criteria for Selecting StudiesCriteria for inclusion were studies reporting breast cancer outcomes in patients treated with tamoxifen and genotyped for polymorphisms in the CYP2D6 gene.ResultsTwenty-five studies of 13,629 individuals were identified, of which 22 investigated the association of CYP2D6 genotype with outcomes in breast cancer women all receiving tamoxifen treatment (“treatment-only” design). Three randomized trials evaluated the effect of CYP2D6 genotype on tamoxifen response (“effect modification” design). In analysis of treatment-only studies, the relative risk (RR) of all-cause mortality (>307 events in 4,936 patients) for carriers of a CYP2D6 reduced function allele was 1.11 (95% confidence interval (CI): 0.94 to 1.31) compared to individuals with normal/increased function CYP2D6 alleles. When we investigated a composite outcome including all-cause mortality and surrogate endpoints for overall survival (>307 events in 6,721 patients), carriers of a CYP2D6 reduced function allele had a RR of 1.27 (95% CI: 1.11 to 1.45). From two randomized trials that permitted effect-modification analysis, one had only 154 patients and showed evidence of effect modification of tamoxifen by CYP2D6 genotype for distant recurrence but was directionally opposite to that predicted, whereas a larger trial of 2,537 patients failed to show evidence of effect modification for breast cancer-free interval (P values for interaction 0.02 and 0.44, respectively).ConclusionsBased on these findings, there is insufficient evidence to recommend CYP2D6 genotyping to guide tamoxifen treatment.

Genetic and Pharmacokinetic Determinants of Response to Transdermal Nicotine in White, Black, and Asian Nonsmokers

The aim of the study was to examine genetic, pharmacokinetic and demographic factors that influence sensitivity to nicotine in never smokers. Sixty never smokers, balanced for gender and race (Caucasian, Blacks and Asian), wore 7 mg nicotine skin patches for up to 8 hours. Serial plasma nicotine concentrations and subjective and cardiovascular effects were measured, and genetic variation in the CYP2A6 gene, the primary enzyme responsible for nicotine metabolism, was assessed. Nicotine toxicity requiring patch removal developed in 9 subjects and was strongly associated with rate of rise and peak concentrations of plasma nicotine. Toxicity, subjective and cardiovascular effects of nicotine were associated with the presence of reduced function CYP2A6 alleles, presumably reflecting slow nicotine metabolic inactivation. This study has implications for understanding individual differences in responses to nicotine medications, particularly when the latter are used for treating medical conditions in non-smokers, and possibly in vulnerability to developing nicotine dependence.

Effects of CYP2C19 genotype on vascular function in patients with coronary artery disease receiving clopidogrel

Purpose: The role of CYP2C19*2 polymorphism in plasma clopidogrel active drug metabolite concentrations, in platelet inhibition and in cardiovascular prognosis has come under question in recent studies. We examined the impact of functional genetic polymorphism CYP2C19*2 on endothelial function and arterial stiffness in patients with CAD treated with clopidogrel regimen. Methods: We consecutively enrolled 408 patients with stable CAD receiving clopidogrel regimen (75mg/d), one month after percutaneous coronary intervention. Endothelial function was evaluated by flow-mediated dilation (FMD) of the brachial artery. Carotid-femoral pulse wave velocity (PWV) was measured as an index of aortic stiffness and augmentation index (AIx) as an index of arterial wave reflections. CYP2C19*2 genotyping was performed by real-time polymerase chain reaction. High on treatment platelet reactivity was evaluated using VerifyNow Assay. VerifyNow reports its results in P2Y12 reaction units (PRU) and the diagnostic cut-off value is 230 PRU. Results: From the study population 150 patients (36.8%) were carriers of at least one CYP2C19*2 reduced-function allele and 258 patients (63.2%) were non carriers. There was no statistically significant difference between carriers and non carriers in age, male sex and the presence of hyperlipidemia, diabetes mellitus, arterial hypertension, in smoking habits, in anticoagulant and statin treatment. Importantly, there was no difference in FMD (4.88±2.34% vs. 4.83±2.21%, p=0.83), PWV (8.53±2.54m/sec vs. 8.85±2.33m/sec, p=0.19) and AIx values (22.87±10.04% vs. 23.82±8.43%, p=0.31) between carriers and non carriers respectively. Finally, carriers of two CYP2C19*2 reduced-function allele had significantly increased PRU (292±53 vs. 198±83, p=0.007). Conclusions: The presence of CYP2C19*2 loss of action polymorphism displays no impact on arterial wall properties in patients with CAD treated with clopidogrel regimen. Moreover, carriers of two CYP2C19 reduced-function alleles had significantly increased platelet reactivity.

Variation in Trans-3′-Hydroxycotinine Glucuronidation Does Not Alter the Nicotine Metabolite Ratio or Nicotine Intake

BackgroundCYP2A6 metabolizes nicotine to its primary metabolite cotinine and also mediates the metabolism of cotinine to trans-3′-hydroxycotinine (3HC). The ratio of 3HC to cotinine (the “nicotine metabolite ratio”, NMR) is an in vivo marker for the rate of CYP2A6 mediated nicotine metabolism, and total nicotine clearance, and has been associated with differences in numerous smoking behaviors. The clearance of 3HC, which affects the NMR, occurs via renal excretion and metabolism by UGT2B17, and possibly UGT2B10, to 3HC-glucuronide. We investigated whether slower 3HC glucuronidation alters NMR, altering its ability to predict CYP2A6 activity and reducing its clinical utility.MethodsPlasma NMR, three urinary NMRs, three urinary 3HC glucuronidation phenotypes and total nicotine equivalents were examined in 540 African American smokers. The UGT2B17 gene deletion and UGT2B10*2 were genotyped.ResultsThe UGT2B17 gene deletion, but not UGT2B10*2 genotype, was associated with slower 3HC glucuronidation (indicated by three 3HC-glucuronidation phenotypes), indicating its role in this glucuronidation pathway. However, neither lower rates of 3HC glucuronidation, nor the presence of a UGT2B17 and UGT2B10 reduced function allele, altered plasma or urinary NMRs or levels of smoking.ConclusionsVariation in 3HC glucuronidation activity, including these caused by UGT2B17 gene deletions, did not significantly alter NMR and is therefore unlikely to affect the clinical utility of NMR in smoking behavior and cessation studies. This study demonstrates that NMR is not altered by differences in the rate of 3HC glucuronidation, providing further support that NMR is a reliable indicator of CYP2A6 mediated nicotine metabolism.