Poor Metabolizer Group Research Articles

Prognostic Impact of CYP2C19 Genotypes on Long-Term Clinical Outcomes in Older Patients After Percutaneous Coronary Intervention.

Carriers of CYP2C19 loss-of-function alleles have increased adverse events after percutaneous coronary intervention, but limited data are available for older patients. We aimed to evaluate the prognostic impact of CYP2C19 genotypes on clinical outcomes in older patients after percutaneous coronary intervention. The study included 1201 older patients (aged ≥75 years) who underwent percutaneous coronary intervention and received clopidogrel-based dual antiplatelet therapy in South Korea. Patients were grouped on the basis of CYP2C19 genotypes. The primary outcome was 3-year major adverse cardiac events, defined as a composite of cardiac death, myocardial infarction, and stent thrombosis. Older patients were grouped into 3 groups: normal metabolizer (36.6%), intermediate metabolizer (48.1%), and poor metabolizer (15.2%). The occurrence of the primary outcome was significantly different among the groups (3.1, 7.0, and 6.2% in the normal metabolizer, intermediate metabolizer, and poor metabolizer groups, respectively; P=0.02). The incidence rate of all-cause death at 3 years was greater in the intermediate metabolizer and poor metabolizer groups (8.1% and 9.2%, respectively) compared with that in the normal metabolizer group (3.5%, P=0.03) without significant differences in major bleeding. In the multivariable analysis, the intermediate metabolizer and poor metabolizer groups were independent predictors of 3-year clinical outcomes. In older patients, the presence of any CYP2C19 loss-of-function allele was found to be predictive of a higher incidence of major adverse cardiac events within 3 years following percutaneous coronary intervention. This finding suggests a need for further investigation into an optimal antiplatelet strategy for older patients. URL: https://clinicaltrials.gov. Identifier: NCT04734028.

Relationships of Proton Pump Inhibitor-Induced Renal Injury with CYP2C19 Polymorphism: A Retrospective Cohort Study.

Proton pump inhibitors (PPIs) have recently been reported to be linked with nephrotoxicity. PPIs are metabolized mainly or partly by cytochrome P450 2C19 (CYP2C19). However, the relationship between CYP2C19 genetic polymorphism and PPI-induced nephrotoxicity is unclear. In this study, we aimed to analyze the association between the time of occurrence of renal injury by PPIs, including lansoprazole, esomeprazole, rabeprazole, and vonoprazan, and CYP2C19 metabolizer status classified by CYP2C19 genotypes. Patients prescribed PPIs were reviewed in this retrospective cohort study. The primary outcome was the time to a 30% decrease in estimated glomerular filtration rate (eGFR) from baseline. In patients treated with lansoprazole, the time to a 30% decrease in eGFR for the CYP2C19 poor metabolizer (PM) group was significantly shorter than that for the non-PM group (hazard ratio for PM vs. non-PM, 2.43, 95% confidence interval, 1.21 to 4.87, P = 0.012). In contrast, in patients that received esomeprazole, rabeprazole, or vonoprazan, no significant differences were found in the time to a 30% decrease in eGFR between non-PM and PM groups. The adjusted hazard ratios for the time to a 30% eGFR decrease in patients treated with lansoprazole were significantly higher for CYP2C19 PM, hypertension, and a history of myocardial infarction. In conclusion, this retrospective study showed that CYP2C19 metabolizer status was associated with the time to a 30% eGFR decrease in patients treated with lansoprazole, but not with esomeprazole, rabeprazole, or vonoprazan.

Effect of CYP3A4*22, CYP3A5*3 and POR*28 genetic polymorphisms on calcineurin inhibitors dose requirements in early phase renal transplant patients.

This study aimed to investigate the combined effect of CYP3A5*3, CYP3A4*22, and POR*28 genetic polymorphisms on tacrolimus and cyclosporine dose requirements. One hundred thirty renal transplant patients placed on either tacrolimus or cyclosporine were recruited, where the effect of CYP3A5*3, CYP3A4*22, and POR*28 genetic polymorphisms on their dose requirements were studied at days 14, 30, and 90 post-transplantations. The POR*28 allele frequency in the studied population was 29.61%. The tacrolimus dose-adjusted trough concentration ratio (C0/D) was significantly lower in the fast metabolizers group ( CYP3A5*1/POR*28(CT/TT ) carriers) than in the poor metabolizers group ( CYP3A5*3/*3/CYP3A4*22 carriers) throughout the study (14, 30, and 90 days) ( P = 0.001, <0.001, and 0.003, respectively). Meanwhile, there was no significant effect of this gene combination on cyclosporine C0/D. Combining the CYP3A5*3, POR*28 , and CYP3A4*22 genotypes can have a significant effect on early tacrolimus dose requirements determination and adjustments. However, it does not have such influence on cyclosporine dose requirements.

Clinical Impact of CYP2C19 Genotype on Clopidogrel-Based Antiplatelet Therapy After Percutaneous Coronary Intervention

BackgroundAlthough there is a growing body of evidence that CYP2C19 genotyping can be beneficial when considering treatment with clopidogrel after percutaneous coronary intervention (PCI), whether a genotype-guided strategy can be generally adopted in routine practice remains unclear among East Asians. ObjectivesThis study sought to investigate long-term outcomes of patients undergoing clopidogrel-based antiplatelet therapy after drug-eluting stent (DES) implantation according to CYP2C19 genotypes. MethodsFrom the nationwide multicenter PTRG-DES (Platelet function and genoType-Related long-term proGnosis in DES-treated patients) consortium, patients who underwent CYP2C19 genotyping were selected and classified according to CYP2C19 loss-of-function allele: rapid metabolizers (RMs) or normal metabolizers (NMs) vs intermediate metabolizers (IMs) or poor metabolizers (PMs). The primary outcome was a composite of cardiac death, myocardial infarction, and stent thrombosis at 5 years after the index procedure. ResultsOf 8,163 patients with CYP2C19 genotyping, 56.7% presented with acute coronary syndrome. There were 3,098 (37.9%) in the RM or NM group, 3,906 (47.9%) in the IM group, and 1,159 (14.2%) in the PM group. IMs or PMs were associated with an increased risk of 5-year primary outcome compared with RMs or NMs (HRadj: 1.42; 95% CI: 1.01-1.98; P = 0.041), and the effect was more pronounced in the first year (HRadj: 1.67; 95% CI: 1.10-2.55; P = 0.016). The prognostic implication of being an IM and PM was significant in acute coronary syndrome patients (HRadj: 1.88; 95% CI: 1.20-2.93; P = 0.005) but not in those with stable angina (HRadj: 0.92; 95% CI: 0.54-1.55; P = 0.751) (interaction P = 0.028). ConclusionsAmong East Asians with clopidogrel-based antiplatelet therapy after DES implantation, CYP2C19 genotyping could stratify patients who were likely to have an increased risk of atherothrombotic events. (Platelet Function and genoType-Related Long-term progGosis in DES-treated Patients: A Consortium From Multi-centered Registries [PTRG-DES]; NCT04734028)

Metoprolol and CYP2D6: A Retrospective Cohort Study Evaluating Genotype-Based Outcomes.

Metoprolol is a medication commonly utilized in select patients to achieve a reduction in heart rate, systolic blood pressure, or other indications. A majority of metoprolol metabolism occurs via CYP2D6. Decreased expression of the CYP2D6 enzyme increases the concentration of metoprolol. Current pharmacogenomics guidelines by the Dutch Pharmacogenomics Working Group recommend slower titrations and dose decreases to minimize adverse effects from poor metabolizers or normal metabolizers taking concomitant medications that are strong inhibitors of CYP2D6 (phenoconverters). This study aimed to evaluate adverse effects such as bradycardia, hypotension, and syncope in patients who are expected to have absent CYP2D6 enzyme activity due to drug-drug or drug-gene interactions. The secondary aims of this study were to evaluate heart rate measurements for the included participants. Retrospective data were collected for individuals with CYP2D6 genotyping results obtained for clinical purposes. Three categories (CYP2D6 normal metabolizers, poor metabolizers, and phenoconverters) were assigned. A total of 325 participants were included. There was no statistically significant difference found in the primary composite outcome between the three metabolizer groups (p = 0.054). However, a statistically significant difference was identified in the incidences of bradycardia between the poor metabolizers and the normal metabolizers or phenoconverters (p < 0.0001). The average heart rates were 2.8 beats per minute (bpm) and 2.6 bpm lower for the poor metabolizer and phenoconverter groups, respectively, compared to the normal metabolizers (p < 0.0001 for both comparisons). This study further supports the role of genetic testing in precision medicine to help individualize patient care as CYP2D6 poor metabolizers taking metoprolol were found to have an increase in bradycardia. Additional research is needed to clarify the dose relationship in this drug-gene interaction.

P2Y12 Reaction Units and Clinical Outcomes in Acute Large Artery Atherosclerotic Stroke: A Multicenter Prospective Study.

We aimed to determine the association between acute platelet reactivity and clinical outcome in acute ischemic stroke (AIS) or transient ischemic attack (TIA) with large-artery atherosclerosis (LAA). In this prospective, 16-multicenter study, we enrolled AIS/TIA patients with LAA receiving clopidogrel. We assessed the association of P2Y12 reaction units (PRU) 24 hours after initiation of antiplatelets with the CYP2C19 genotype and recurrent ischemic stroke within 90 days, and the difference between acute (≤ 7 days) and subacute (8-90 days) phases. Among the 230 AIS/TIA patients enrolled, 225 with complete outcome data and 194 with genetic results were analyzed. A higher PRU was significantly associated with recurrent ischemic stroke within 90 days (frequency, 16%), and within 7 days (10%). Twenty-nine patients (15%) belonged to a CYP2C19 poor metabolizer group (CYP2C19 ＊2/＊2, ＊2/＊3, or ＊3/＊3). Multivariable receiver-operating characteristic analysis showed a greater area-under-the-curve (AUC) in predicting recurrence within 7 days, compared to 8-90 days (AUC, 0.79 versus 0.64; p=0.07), with a cut-off PRU of 254. Multivariable analysis showed high PRU (≥ 254), which had a comparable predictive performance for recurrent ischemic stroke within 7 days (odds ratio, 6.82; 95% CI, 2.23-20.9; p＜0.001) to the CYP2C19 poor metabolizer genotype. The net reclassification improvement, calculated by adding high PRU (≥ 254) to a model including the CYP2C19 poor metabolizer genotype in the prediction of recurrence within 7 days, was 0.83 (p＜0.001). Acute PRU evaluation possesses predictive value for recurrent ischemic stroke, especially within 7 days in AIS/TIA with LAA.

CYP2C19 metabolizer phenotypes may affect the efficacy of statins on lowering small dense low-density lipoprotein cholesterol of patients with coronary artery disease.

Dyslipidemia is a major cause of arteriosclerotic cardiovascular disease (ASCVD), and low-density lipoprotein cholesterol (LDL-C) is the profile to be reduced to prevent disease progression. Small dense low-density lipoprotein cholesterol (sdLDL-C) has been proven to be a more effective biomarker than LDL-C for ASCVD primary and secondary prevention. CYP2C19 is an important drug metabolism gene. This study aimed to investigate the relationship between sdLDL-C and coronary artery disease (CAD) risk factors and explore the influence of CYP2C19 metabolizer phenotypes on the sdLDL-C lowering efficacy of statins. This study recruited 182 patients with CAD and 200 non-CAD controls. Baseline laboratory indices of fasting blood were detected, including blood lipids, glucose, and creatinine. In addition, LDL-C subfractions were separated and quantified. Gene polymorphisms of SLCO1B1 and CYP2C19 were detected in patients with CAD. The LDL-C subfractions levels of patients with CAD were followed up after statin drug treatment. Total cholesterol, LDL-C, LDLC-2, LDLC-3, LDLC-4, LDLC-5, LDLC-6, LDLC-7, and sdLDL-C levels of patients with CAD were significantly higher than those in non-CAD controls. Meanwhile, sdLDL-C (AUC = 0.838) and LDLC-4 (AUC = 0.835) performed outstandingly in distinguishing patients with CAD from controls. Based on CYP2C19 metabolizer phenotypes, 113 patients with CAD were divided into the extensive metabolizer (EM, n = 49), intermediate metabolizer (IM, n = 52), and poor metabolizer (PM, n = 12) groups. The patients with IM and PM metabolizer phenotypes had better sdLDL-C lowering efficacy after taking statin drugs than patients with EM phenotype (P = 0.0268, FDR = 0.0536). The SLCO1B1 genotype had no significant impact on the efficacy of statins (P = 0.1611, FDR = 0.1611). sdLDL-C and LDLC-4 outperformed other blood lipids such as LDL-C for CAD risk screening. CYP2C19 metabolizer phenotypes had the potential to predict the efficacy of statins in lowering sdLDL-C.

Combined Effect of CYP2C19 Genetic Polymorphisms and C-Reactive Protein on Voriconazole Exposure and Dosing in Immunocompromised Children.

BackgroundPediatric patients have significant interindividual variability in voriconazole exposure. The aim of the study was to identify factors associated with voriconazole concentrations and dose requirements to achieve therapeutic concentrations in pediatric patients.MethodsMedical records of pediatric patients were retrospectively reviewed. Covariates associated with voriconazole plasma concentrations and dose requirements were adjusted by using generalized linear mixed-effect models.ResultsA total of 682 voriconazole steady-state trough concentrations from 91 Chinese pediatric patients were included. Voriconazole exposure was lower in the CYP2C19 normal metabolizer (NM) group compared with the intermediate metabolizer (IM) group and the poor metabolizer (PM) group (p = 0.0016, p < 0.0001). The median daily dose of voriconazole required to achieve therapeutic range demonstrated a significant phenotypic dose effect: 20.8 mg/kg (range, 16.2–26.8 mg/kg) for the CYP2C19 NM group, 18.2 mg/kg (range, 13.3–21.8 mg/kg) for the CYP2C19 IM group, and 15.2 mg/kg (range, 10.7–19.1 mg/kg) for the CYP2C19 PM group, respectively. The extent of impact of C-reactive protein (CRP) levels on voriconazole trough concentrations and dose requirements varied between CYP2C19 phenotypes. Increases of 20, 120, 245, and 395 mg/L from 5 mg/L in CRP levels were associated with increases in voriconazole trough concentration by 22.22, 50, 64.81, and 75% respectively, in the NM group; by 39.26, 94.48, 123.93, and 146.63%, respectively, in the IM group; and by 17.17, 37.34, 46.78, and 53.65%, respectively, in the PM group. Meanwhile, increases of 20, 120, 245, and 395 mg/L from 5 mg/L in CRP levels were associated with increases in voriconazole dose requirements by 7.15, 14.23, 17.35, and 19.43%, respectively, in the PM group; with decreases in voriconazole dose requirements by 3.71, 7.38, 8.97, and 10.03%, respectively, in the NM group; and with decreases by 4, 9.10, 11.05, and 12.35%, respectively, in the IM group. In addition, age and presence of immunosuppressants had significant effects on voriconazole exposure.ConclusionsOur study suggests that CYP2C19 phenotypes, CRP concentrations, age, and the presence of immunosuppressants were factors associated with the pharmacokinetic changes in voriconazole. There was heterogeneity in the effect of CRP on voriconazole plasma concentrations across different CYP2C19 genotypes. Combining relevant factors with dose adaptation strategies in therapeutic drug monitoring may help to reduce the incidence of subtherapeutic and supratherapeutic concentrations in clinical practice.

Association of CYP2C19 Polymorphism With Proton Pump Inhibitors Effectiveness and With Fractures in Real-Life: Retrospective Cohort Study.

Symptom refractoriness of patients treated with proton pump inhibitors (PPIs) might be explained by polymorphism in CYP2C19. This is a retrospective cohort study in which we used the computerized database of Clalit Health Services to compose a cohort from cancer case‐control studies’ participants that had been genotyped, and that have been dispensed PPI (January 1, 2002 to November 10, 2020). We retrieved demographic and clinical variables on date of PPI initiation (cohort entry), and studies’ questionnaires‐reported consumption of foods/beverages known to increase peptic‐related symptoms. Primary outcome was an abdominal pain diagnosis; secondary outcome was a composite of abdominal pain, visit to a gastroenterology clinic, change to another PPI, PPI dose increase, or metoclopramide prescription, reflecting symptoms persistence/recurrence; in a 2‐year follow‐up. We also evaluated the association between genetic groups and hip/wrist/spine fractures, in a long‐term follow‐up. Of 3,326 PPI initiators, there were 66 (2.0%), 739 (22.2%), 1394 (41.9%), 947 (28.5%), and 180 (5.4%) CYP2C19 poor, intermediate, normal, rapid, and ultra‐rapid metabolizers, respectively. Being a poor metabolizer was associated with lower risk for the primary outcome, hazard ratio (HR) = 0.50 (95% confidence interval (CI) 0.27–0.91), HR = 0.52 (95% CI 0.28–0.94); and for the secondary outcome, HR = 0.57 (95% CI 0.38–0.86), HR = 0.58 (95% CI 0.39–0.87), in univariate and multivariable cox regression analyses, respectively. In long‐term follow‐up with 20,142 person‐years of follow‐up: 7.6% (5 cases) within the poor metabolizers group, and 11.6%, 12.9%, 12.8%, and 11.1% in the normal, intermediate, rapid, and ultra‐rapid metabolizers groups, respectively, had a new fracture (nonsignificant). We conclude that CYP2C19 poor metabolizer status is associated with higher effectiveness of PPIs, and is not associated with higher risk for fractures.

Metabolomics reveals biomarkers in human urine and plasma to predict cytochrome P450 2D6 (CYP2D6) activity.

Background and PurposeIndividualized assessment of cytochrome P450 2D6 (CYP2D6) activity is usually performed through phenotyping following administration of a probe drug to measure the enzyme's activity. To avoid any iatrogenic harm (allergic drug reaction, dosing error) related to the probe drug, the development of non‐burdensome tools for real‐time phenotyping of CYP2D6 could significantly contribute to precision medicine. This study focuses on the identification of markers of the CYP2D6 enzyme in human biofluids using an LC‐high‐resolution mass spectrometry‐based metabolomic approach.Experimental ApproachPlasma and urine samples from healthy volunteers were analysed before and after intake of a daily dose of paroxetine 20 mg over 7 days. CYP2D6 genotyping and phenotyping, using single oral dose of dextromethorphan 5 mg, were also performed in all participants.Key ResultsWe report four metabolites of solanidine and two unknown compounds as possible novel CYP2D6 markers. Mean relative intensities of these features were significantly reduced during the inhibition session compared with the control session (n = 37). Semi‐quantitative analysis showed that the largest decrease (−85%) was observed for the ion m/z 432.3108 normalized to solanidine (m/z 398.3417). Mean relative intensities of these ions were significantly higher in the CYP2D6 normal–ultrarapid metabolizer group (n = 37) compared with the poor metabolizer group (n = 6). Solanidine intensity was more than 15 times higher in CYP2D6‐deficient individuals compared with other volunteers.Conclusion and ImplicationsThe applied untargeted metabolomic strategy identified potential novel markers capable of semi‐quantitatively predicting CYP2D6 activity, a promising discovery for personalized medicine.

Influence of CYP2C19 Polymorphisms on the Pharmacokinetics of Omeprazole in Elderly Subjects.

Omeprazole blocks the gastric H+ /K+ adenosine triphosphatase, thus inhibiting gastric acid secretion, and is metabolized by cytochrome P450 (CYP) 2C19. Due to the physiological changes in the elderly, there are different pharmacokinetic consequences compared to young people. The aim of this study was to evaluate the pharmacokinetic profiles of omeprazole in 15 elderly participants according to the CYP2C19 genotype. The concentration-time profiles of omeprazole and its metabolites, 5-hydroxy (5-OH) omeprazole and omeprazole sulfone, were similar between the CYP2C19 extensive metabolizer (EM) and intermediate metabolizer groups. In contrast, when comparing the EM group and CYP2C19 poor metabolizer (PM) group, the EM/PM geometric mean ratio (95% confidence interval) of area under the plasma concentration-time curve from time of dosing to the last measurable concentration was 0.52 (0.27-1.01) and that of the IM group was 0.71 (0.32-1.59), indicating that the exposure of omeprazole in the PM group was increased. The exposure of 5-OH omeprazole was significantly decreased in the PM group when compared to the EM group, with an EM/PM geometric mean ratio (95% confidence interval) of 2.20 (1.50-3.22). In conclusion, the tendency of drug exposure according to the CYP2C19 genotype in the elderly and young adults was similar in that the exposure level was highest in the PM group. However, when compared to young adults, the difference between the genotype groups was smaller in the elderly.

CYP2D6 Reduced Function Variants and Genotype/Phenotype Translations of CYP2D6 Intermediate Metabolizers: Implications for Personalized Drug Dosing in Psychiatry.

Genetic differences in cytochrome P450 (CYP)-mediated metabolism have been known for several decades. The clinically most important polymorphic CYP enzyme is CYP2D6, which plays a key role in the metabolism of many antidepressants and antipsychotics, along with a range of non-psychiatric medications. Dose individualization based on CYP2D6 genotype to improve the effect and safety of drug treatment has been an ambition for a long time. Clinical use of CYP2D6 genotyping is steadily increasing; however, for pre-emptive genotyping to be successful in predicting individual dose requirements, high precision of genotype-to-phenotype translations are required. Recently, guidelines for assigning CYP2D6 enzyme activity scores of CYP2D6 variant alleles, and subsequent diplotype-to-phenotype translations, were published by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group. Consensus on assigning activity scores of CYP2D6 variant alleles and translating diplotype scores into CYP2D6 poor, intermediate, normal, or ultrarapid metabolizer groups were obtained by consulting 37 international experts. While assigning enzyme activities of non-functional (score 0) and fully functional (score 1) alleles are straightforward, reduced function variant alleles are more complex. In this article, we present data showing that the assigned activity scores of reduced function variant alleles in current guidelines are not of sufficient precision; especially not for CYP2D6*41, where the guideline activity score is 0.5 compared to 0.05–0.15 in pharmacogenetic studies. Due to these discrepancies, CYP2D6 genotypes with similar guidelinediplotype scores exhibit substantial differences in CYP2D6 metabolizer phenotypes. Thus, it is important that the guidelines are updated to be valid in predicting individual dose requirements of psychiatric drugs and others metabolized by CYP2D6.

CYP2C19 Polymorphisms in Indonesia: Comparison among Ethnicities and the Association with Clinical Outcomes.

Simple SummaryCYP2C19 is known as an enzyme primarily responsible for metabolizing various drugs, such as proton pump inhibitor, antiplatelet, anti-epileptic, and anticoagulant. CYP2C19 is known to be polymorphic and can result in the clinical efficacy of drugs. To examine the prevalence and the distribution of the CYP2C19 genetic polymorphisms in Indonesia, we performed polymerase chain reaction-restriction fragment length polymorphism to the genomic DNA of Indonesian participants. In addition, we also analyzed the distribution of CYP2C19 polymorphisms among ethnicities and clinical outcomes. We found that the prevalence of intermediate metabolizers were the highest in Indonesia, followed by rapid metabolizers and poor metabolizers, respectively. The distribution of metabolizer groups were different between ethnic groups in Indonesia. Therefore, dosage adjustment should be considered when administering drugs-affected by CYP2C19 in Indonesia. The results presented in this study showed the distribution of CYP2C19 variant alleles at the population level in Indonesia and might be used as a consideration for providing personalized treatment in clinical practice.CYP2C19 polymorphisms are important factors for proton pump inhibitor-based therapy. We examined the CYP2C19 genotypes and analyzed the distribution among ethnicities and clinical outcomes in Indonesia. We employed the polymerase chain reaction-restriction fragment length polymorphism method to determine the CYP2C19 genotypes and evaluated inflammation severity with the updated Sydney system. For CYP2C19*2, 46.4% were the homozygous wild-type allele, 14.5% were the homozygous mutated allele, and 39.2% were the heterozygous allele. For CYP2C19*3, 88.6% were the homozygous wild-type allele, 2.4% were the homozygous mutated allele, and 9.0% were the heterozygous allele. Overall, the prevalence of rapid, intermediate, and poor metabolizers in Indonesia was 38.5, 41.6, and 19.9%, respectively. In the poor metabolizer group, the frequency of allele *2 (78.8%) was higher than the frequency of allele *3 (21.2%). The Papuan had a significantly higher likelihood of possessing poor metabolizers than the Balinese (OR 11.0; P = 0.002). The prevalence of poor metabolizers was lower compared with the rapid and intermediate metabolizers among patients with gastritis and gastroesophageal reflux disease. Intermediate metabolizers had the highest prevalence, followed by rapid metabolizers and poor metabolizers. Dosage adjustment should therefore be considered when administering proton pump inhibitor-based therapy in Indonesia.

Association between CYP2C19 polymorphisms and clinical outcomes in patients undergoing stent procedure for cerebral artery stenosis

We investigated the effect of CYP2C19 polymorphisms on the clinical outcomes of clopidogrel therapy in patients after stenting procedure for cerebral artery stenosis in northeast China. 568 patients performed CYP2C19 genotype screening in the neurosurgery department of our hospital; 154 patients were finally recruited according to the inclusion and exclusion criteria, and followed-up for 6 months. Ischemic events including (1) transient ischemic attack (TIA); (2) stent thrombosis; (3) ischemic stroke; and (4) death were defined as primary clinical endpoints. The frequencies of CYP2C19*1, *2 and *3 alleles in 568 patients were 63.1%, 31.1% and 5.8%, respectively. 154 patients were classified into extensive (65 patients; 42.2%), intermediate (66 patients; 42.9%), and poor (23 patients; 14.9%) metabolizer groups. A χ2 test showed a significant difference in primary clinical endpoints at 6 months (P = 0.04), and a multivariate Cox regression analysis indicated that the CYP2C19 loss-of-function (LOF) alleles associated with post-procedure prognosis. The Kaplan–Meier curve revealed that there was no significant difference in ischemic events between *2 and *3 alleles carriers. Our study verifies that CYP2C19 *2 and *3 have significant impact on the clinical outcomes of clopidogrel therapy in patients with stenting procedure for cerebral artery stenosis in China.

Effects of individualized antiplatelet therapy, based on CYP2C19 genotyping, on platelet function in patients underwent percutaneous coronary intervention.

To evaluate the effect of individualized antiplatelet therapy, based on CYP2C19 genotyping, on platelet function in patients underwent PCI and to compare this treatment with conventional antiplatelet therapy. All patients were treated with 100 mg aspirin once a day. Additionally, the CA group received 75 mg clopidogrel once a day. The IA group was divided into extensive metabolizers (EMs, no loss-of-function, i.e. LOF allele, 75 mg clopidogrel once a day), intermediate metabolizers (IMs, carrying one LOF alleles, 75 mg clopidogrel twice daily), and poor metabolizers group (PMs, carrying two LOF alleles, 90 mg ticagrelor twice daily). After taking these antiplatelet medications for ⩾5 days, we assessed platelet function by thromboelastography, and recorded the MAADP (maximum amplitude produced by adenosine diphosphate) value. MAADP > 47 mm was defined as residual HPR, indicating a high risk of thrombosis. MAADP ≤ 31 mm indicated a high risk of bleeding. The proportion of patients with MAADP > 47 mm was significantly lower in the IA group (29.6%) than the CA group (38.1%). The proportion of patients with MAADP ≤ 31 mm was significantly higher in the IA group (31.0%) than the CA group (21.3%). No significant differences were found in the proportions of patients with MAADP > 47 mm or MAADP ≤31 mm when compared between the EMs and IMs group. Individualized antiplatelet therapy, based on CYP2C19 genotyping, can reduce the incidence of HPR in ACS patients after PCI compared to conventional therapy. By taking a double dose of clopidogrel, patients with a CYP2C19 LOF allele can therefore overcome the reduced efficacy of clopidogrel associated with LOF alleles without increasing the risk of bleeding, which is of guiding significance for the management of antiplatelet therapy on ACS patients after PCI especially considering the CYP2C19 LOF alleles that carry an important predictor for the ischemic events. chiCTR-INC-17011550.

CYP2C19, PON1, and ABCB1 gene polymorphisms in Han and Uygur populations with coronary artery disease in Northwestern Xinjiang, China, From 2014 Through 2019.

The morbidity of coronary artery disease (CAD) in the Uygur population of Xinjiang was much higher than the national average. Clopidogrel is the most commonly used medication worldwide in dual antiplatelet therapy for CAD, and the response of clopidogrel is affected by CYP2C19, PON1, and ABCB1 genetic polymorphisms. The distribution of CYP2C19∗17, ABCB1, and PON1 genetic polymorphisms in Han and Uygur populations with CAD of Xinjiang has not been investigated.This study aimed to investigate the frequencies of CYP2C19, PON1, and ABCB1 genetic polymorphisms, and to identify the metabolizer phenotype of CYP2C19 in Han and Uygur populations with CAD in Northwestern Xinjiang, China. We identified 602 Han and 527 Uygur patients from 2014 through 2019 and studied genotypes for selected allele polymorphisms using sequencing by hybridization.There were significantly different allele frequencies and genotype frequencies between the 2 ethnic groups in terms of CYP2C19∗2, ∗3, ∗17, ABCB1 and PON1, (P < .05). For CYP2C19∗17, the frequency of TT genotype was 2.5% in Uygur patients, but it was undetectable in Han patients. In both the intermediate and poor metabolizer groups, the genotypes polymorphisms CYP2C19∗2, ∗3, ∗17 were significantly less common in Uygur patients than in Han patients (P < .001). By contrast, the proportion of ultra-metabolizers as defined by CYP2C19∗2, ∗3, ∗17 polymorphisms significantly higher in Uygur patients (18.6%) than in Han patients (1.7%, P < .001). The CYP2C19∗2 frequency was significantly different between Han patients and Han healthy groups (P < .001), while the CYP2C19∗3 frequency was significantly different between Uygur patients and Uygur healthy groups (P < .001).Our study supports the notion of interethnic differences in terms of CYP2C19, PON1, and ABCB1 polymorphisms and CYP2C19 genotype-defined clopidogrel metabolic groups. These finding could provide valuable data and insights into personalized CAD treatment for the Uygur and Han populations in Xinjiang.

CYP2D6 Genetic Polymorphisms and Risperidone Pharmacokinetics: A Systematic Review and Meta-analysis.

Risperidone is a second-generation antipsychotic drug metabolized to an active metabolite, 9-hydroxyrisperidone, primarily by cytochrome P450 (CYP) 2D6 and to a lesser extent by CYP3A4. The extent to which drug metabolism genetics impacts risperidone and 9-hydroxyrisperidone exposure has not been clarified. A systematic review and meta-analysis evaluated the impact of genetically defined CYP2D6 function on risperidone pharmacokinetics applying a standardized genotype-phenotype translation system. A comprehensive electronic database search identified studies reporting relationships between genetically determined CYP2D6 metabolism and risperidone pharmacokinetic properties. The exposure of risperidone or active moiety (risperidone+9-hydroxyrisperidone) was measured by dose-adjusted steady-state serum or plasma concentration or area under the concentration-time curve as primary outcomes. Subjects were assigned to CYP2D6 poor metabolizer, intermediate metabolizer, normal metabolizer, or ultrarapid metabolizer groups using a standardized genotype-phenotype translation method. Effect sizes between groups were pooled and stratified by single or multiple dosing regimens. A total of 15 studies involving 2125 adult subjects were included in the meta-analysis. Following multiple-dose oral administration, compared with CYP2D6 normal metabolizers, the risperidone dose-adjusted steady-state serum/plasma concentration was 2.35-fold higher in intermediate metabolizers (95% confidence interval [CI] 1.77-3.13, p<0.0001) and 6.20-fold higher in poor metabolizers (95% CI 5.05-7.62, p<0.0001); the active moiety dose-adjusted steady-state concentration was 1.18-fold higher in intermediate metabolizers (95% CI 1.11-1.25, p<0.0001) and 1.44-fold higher in poor metabolizers (95% CI 1.23-1.69, p<0.0001). Higher area under the concentration-time curve of risperidone and active moiety was also found in single-dose studies. Genetically defined impaired CYP2D6 activity is associated with increased exposure of both risperidone and risperidone+9-hydroxyrisperidone in adults receiving oral formulations. Additional studies are needed to quantify the clinical impact of these relationships.

Impact of flavin-containing monooxygenase 3 and CYP2C19 genotypes on plasma disposition and adverse effects of voriconazole administered orally in immunocompromised patients

Flavin-containing monooxygenase (FMO) 3 together with cytochrome P450 (CYP) 2C19 play a significant role in voriconazole N-oxidation. This study aimed to evaluate the influence of FMO3 and CYP2C19 genotypes on the plasma disposition and adverse effects of voriconazole in immunocompromised patients. Sixty-five Japanese immunocompromised patients receiving oral voriconazole were enrolled. Predose plasma concentrations of voriconazole and N-oxide were determined at day 5 or later. The adverse effects of voriconazole and the FMO3 and CYP2C19 genotypes were investigated. The patients with FMO3 E158K/E308G had a lower plasma concentration of voriconazole. The metabolic ratio to N-oxide was significantly higher in the FMO3 E158K/E308G group than in the wild group. In contrast, FMO3 V257M was not associated with the plasma concentration of voriconazole. No significant difference was observed in the saturation index, defined as a correlation coefficient of the regression line between the absolute plasma concentration of voriconazole and the inverse value of the metabolic ratio to N-oxide, between the FMO3 genotypes. CYP2C19 phenotype did not affect the plasma concentration and metabolic ratio of voriconazole. The saturation index of voriconazole rose in the order of CYP2C19 extensive, intermediate, and then poor metabolizer groups. However, the FMO3 and CYP2C19 genotypes and their associated voriconazole pharmacokinetics did not have an effect on the incidence of adverse effects. In conclusion, FMO3 E158K/E308G decreased the plasma concentration of voriconazole through its higher metabolic activity. The FMO3 genotype altered the plasma exposure of voriconazole, while the CYP2C19 phenotype affected the metabolic capacity in immunocompromised patients.

Pharmacogenetic impact of docetaxel on neoadjuvant treatment of breast cancer patients.

This study aimed to investigate the effect of CYP3A4 and CYP3A5 genotypes on clinical outcomes of docetaxel treatment. In the PROMIX trial, 150 breast cancer patients received docetaxel preoperatively. CYP3A4 and CYP3A5 genotype combinations were transformed into total CYP 3A phenotypes. Seven patients were characterized as poor metabolizer (PM), 22 patients as extensive metabolizer and 121 patients as intermediate metabolizer.The frequency of grade 3/grade 4 adverse events was higher in the PM group (p=0.002). One PM subject who basically lacked enzyme activity died from typhlitis. Total45recurrences were reported after a median of 5-year follow-up; none of these was PM. The allelic variants CYP3A4*22 and CYP3A5*3 contribute to the interpatient variations of docetaxel.

Effect of CYP2D6 Poor Metabolizer Phenotype on Stereoselective Nebivolol Pharmacokinetics.

Nebivolol is a drug available as a racemate of d-nebivolol (SRRR) and lnebivolol (RSSS). In human liver microsomes, CYP2D6 mainly catalyses the metabolism of lnebivolol, while CYP2C19 catalyses the metabolism of d-nebivolol. Nebivolol stereoselective pharmacokinetics has been described only for extensive metabolizers (EM). To describe the stereoseletive nebivolol pharmacokinetics in CYP2D6 poor metabolizers (PM) and to assess whether the phenotype has an impact on nebivolol pharmacokinetics. Three healthy volunteers PM phenotyped (ratios of 20.1, 220 and 244 for the 8 h urinary excretion of metoprolol/alfa-hydroxymetoprolol) received a single oral dose of racemic nebivolol and sequential blood samples were collected between zero (predose) and 48 h. The obtained data were compared to 22 EM subjects with normal kidney function enrolled in our previous study. For both isomers, Cmax, Tmax and AUC0-48 were significantly greater in the PM group compared to the EMs (p = 0.006 - 0.001). For d-nebivolol, Cmax, Tmax and AUC0-48 were, on average, 5.9, 2.7 and 15.0 larger in PMs. The corresponding values for l-nebivolol were 4.4, 2.7 and 17.5. The decline in plasma concentration of both nebivolol isomers in PM phenotypes, especially those with MR of 220 and 244, which indicate minimal or absent CYP2D6 activity, points to alternative mechanisms for nebivolol elimination. Collectively, our results are the first to show the significant impact of CYP2D6 PM phenotype on the metabolic disposition and in vivo exposure to both nebivolol isomers.