Prediction of the Impact of CYP2C19 Polymorphism on Drug-Drug Interaction between Voriconazole and Tacrolimus Using Physiologically-Based Pharmacokinetic Modelling

Abstract Voriconazole increases tacrolimus blood concentration significantly when coadministrated. The recommendation of reducing tacrolimus to 1/3 in voriconazole package insert seems not to be satisfactory in clinical practice. In vitro studies demonstrated that the magnitude of inhibition depends on the concentration of voriconazole, while voriconazole exposure is determined by the genotype status of CYP2C19. CYP2C19 gene polymorphism challenges the management of drug-drug interactions(DDIs) between voriconazole and tacrolimus. This work aimed to predict the impact of CYP2C19 polymorphism on the DDIs by using physiologically based pharmacokinetics (PBPK) models. The precision of the developed voriconazole and tacrolimus models was reasonable by evaluating the pharmacokinetic parameters fold error, such as AUC0-24, Cmax and tmax. Voriconazole increased tacrolimus concentration immediately in all population. The simulated duration of DDIs disappearance after voriconazole withdrawal were 146h, 90h and 66h in poor metabolizers (PMs), intermediate metabolizers (IMs) and extensive metabolizers(EMs), respectively. The developed and optimized PBPK models in this study can be applied to assit the dose adjustment for tacrolimus with and without voriconazole.

Effect of antiplatelet strategy on prognosis of in patients with diabetes mellitus and acute coronary syndrome with different CYP2C19 genotype / 国际生物医学工程杂志

Objective:To investigate the effect of different P2Y12 inhibitors on the long-term prognosis of patients with diabetes mellitus (DM) and acute coronary syndrome (ACS), with or without the CYP2C19 loss-of-function (LOF) gene. Method:266 consecutive ACS patients undergoing percutaneous coronary intervention (PCI) were enrolled. According to the CYP2C19 LOF genotype, the patients were divided into rapid metabolizing-type (without the CYP2C19 LOF gene) and moderate-slow metabolizing type (with the CYP2C19 LOF gene). Each type was divided into the A group (with diabetes) and the B group (without diabetes). Each group was divided into the ticagrelor subgroup and the clopidogrel subgroup according to the type of P2Y12 platelet inhibitor. The MACE events were recorded for each subgroup over 3 years, and the prognostic impact of the CYP2C19 LOF genotype and the type of P2Y12 used were analyzed. Results:There were no significant differences in MACE, revascularization, stroke, heart failure rehospitalization, major bleeding, or all-cause mortality among subgroups of patients with rapid metabolizing type at 3 years after PCI (all P>0.05). In patients with moderate-slow metabolizing-type, the use of tegretol significantly reduced the probability of MACE events and cardiac revascularization (all P<0.01) and significantly reduced the reoccurrence of heart attack in patients with DM. Conclusions:In DM combined with ACS patients with rapid metabolizing type, the choice of different P2Y12 inhibitors after PCI had no significant effect on their prognosis. In DM combined with ACS patients with moderate-slow metabolizing type, tegretol not only significantly reduced the incidence of MACE, revascularization, and reinfarction, but also did not increase the risk of major bleeding. In terms of reducing the reoccurrence of heart attack, the benefit of using tegretol in the DM patients was greater than in the non-DM patients.

Antiplatelet and myocardial protective effect of Shexiang Tongxin Dropping Pill in patients undergoing percutaneous coronary intervention: A randomized controlled trial / 中西医结合学报

BACKGROUND@#High on-clopidogrel platelet reactivity could be partially explained by loss-of-function alleles of CYP2C19, the enzyme that converts clopidogrel into its active form. Shexiang Tongxin Dropping Pill (STDP) is a traditional Chinese medicine to treat angina pectoris. STDP has been shown to improve blood flow in patients with slow coronary flow and attenuate atherosclerosis in apolipoprotein E-deficient mice. However, whether STDP can affect platelet function remains unknown.@*OBJECTIVE@#The purpose of this study is to examine the potential effects of STDP on platelet function in patients undergoing percutaneous coronary intervention (PCI) for unstable angina. The interaction between the effects of STDP with polymorphisms of CYP2C19 was also investigated.@*DESIGN, PARTICIPANTS AND INTERVENTION@#This was a single-center, randomized controlled trial in patients undergoing elective PCI for unstable angina. Eligible subjects were randomized to receive STDP (210 mg per day) plus dual antiplatelet therapy (DAPT) with clopidogrel and aspirin or DAPT alone.@*MAIN OUTCOME MEASURES@#The primary outcome was platelet function, reflected by adenosine diphosphate (ADP)-induced platelet aggregation and platelet microparticles (PMPs). The secondary outcomes were major adverse cardiovascular events (MACEs) including recurrent ischemia or myocardial infarction, repeat PCI and cardiac death; blood biomarkers for myocardial injury including creatine kinase-MB isoenzyme (CK-MB) and high-sensitive troponin I (hsTnI); and biomarkers for inflammation including intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), monocyte chemoattractant protein-1 (MCP-1) and galectin-3.@*RESULTS@#A total of 118 subjects (mean age: [66.8 ± 8.9] years; male: 59.8%) were included into analysis: 58 in the control group and 60 in the STDP group. CYP2C19 genotype distribution was comparable between the 2 groups. In comparison to the control group, the STDP group had significantly lower CK-MB (P < 0.05) but similar hsTnI (P > 0.05) at 24 h after PCI, lower ICAM-1, VCAM-1, MCP-1 and galectin-3 at 3 months (all P < 0.05) but not at 7 days after PCI (P > 0.05). At 3 months, the STDP group had lower PMP number ([42.9 ± 37.3] vs. [67.8 ± 53.1] counts/μL in the control group, P = 0.05). Subgroup analysis showed that STDP increased percentage inhibition of ADP-induced platelet aggregation only in slow metabolizers (66.0% ± 20.8% in STDP group vs. 36.0% ± 28.1% in the control group, P < 0.05), but not in intermediate or fast metabolizers. The rate of MACEs during the 3-month follow-up did not differ between the two groups.@*CONCLUSION@#STDP produced antiplatelet, anti-inflammatory and cardioprotective effects. Subgroup analysis indicated that STDP inhibited residual platelet reactivity in slow metabolizers only.@*TRIAL REGISTRATION@#This study was registered on www.chictr.org.cn: ChiCTR-IPR-16009785.

Clinical study on traditional Chinese medicine constitution types and CYP2C19 gene polymorphism in acute cerebral infarction / 国际中医中药杂志

Objective@#To investigate the correlation between Traditional Chinese medicine (TCM) constitution classification and clopidogrel-related CYP2C19 gene polymorphism of acute cerebral infarction patients.@*Methods@#A cross-sectional method was used in this study. Patients with acute cerebral infarction were screened and enrolled according to our inclusion and exclusion criteria. TCM constitution were evaluated in patients with acute cerebral infarction. Digital fluorescence hybridization Technology was used to test genotypes of CYP2C19 and Hardy-Weinberg’s equilibrium was used to examine CYP2C19 gene polymorphism of the patients. Binary logistic regression analysis method was used to explore the relationship between TCM constitution types and clopidogrel-related CYP2C19 gene polymorphism in acute cerebral infarction.@*Results@#Among the 100 patients with acute cerebral infarction, 18 belong to Yang-deficiency constitution (18 cases, 18%), 30 Yin-deficiency (30 cases, 30%), 18 belong to Qi-deficiency constitution (18 cases, 18%), 51 belong to phlegm-dampness constitution(51 cases, 51%), 14 belong to damp-heat constitution (14 cases, 14%), 2 belong to special constitution (2 cases, 2%), blood-stasis constitution (27 cases, 27%), Qi stagnation constitution (4 cases, 4%), and normal constitution (11 cases, 11%). The CYP2C19*2 gene polymorphism distribution: CYP2C19*2 (A/A, mutant homozygous) (21 cases, 21%), CYP2C19*2 (A/G, mutant heterozygote) (33 cases, 33%), CYP2C19*2 (G/G) (normal homozygous) (46 cases, 46%). The mutant allele frequency was 0.375. Binary logistic regression analysis showed that compared with A/A genotype, the G/G genotype of CYP2C19*2 in acute cerebral infarction was correlated with phlegm-dampness constitution (OR=5.105, 95% CI: 1.308-19.928, P<0.05) and blood-stasis constitution (OR=12.557, 95% CI: 1.741-90.558, P<0.05).@*Conclusions@#The proportion of phlegm-dampness constitution is the highest in patients with acute cerebral infarction. The mutation rate of clopidogrel-related CYP2C19*2 was significantly higher than that of CYP2C19*3 clopidogrel-related CYP2C19*2 gene polymorphism might be related to phlegm-dampness constitution and blood-stasis constitution.

Correlation study between cytochrome P4502C19 gene polymorphism or metabolic type and ADP induced-platelet aggregation inhibition and clopidogrel resistance / 中国临床药理学与治疗学

AIM: To investigate the effect of the polymorphism and metabolic type of cytochrome P450 (CYP) 2C19 gene on the inhibitory rate of platelet aggregation induced by ADP and relationship with resistance of clopidogrel. METHODS: A total of 163 patients that are administrated with aspirin and clopidogrel were collected from the Yijishan Hospital of Wannan Medical College from June 2016 to July 2017. The CYP2C19*2, *3 and *17 genotypes of patients were detected with fluorescence staining in situ hybridization, according to the genotype, CYP2C19 enzyme activity was divided into fast metabolic (RM), intermediate metabolic (IM), slow metabolic (PM) and ultrafast metabolic type (UM). After 5 days of drug delivery, the platelet aggregation inhibition rate (IPAADP) induced by ADP was detected by thrombus elasto graph. IPAADP differences between CYP2C19*2, *3 and *17 genotype and CYP2C19 enzyme metabolic type were evaluated. CYP2C19 genotype and metabolic type as well as their distribution in clopidogrel resistance group (CR) and non clopidogrel resistance group (NCR) were observed. RESULTS: The mutation rates of CYP2C19*2, *3 and *17 were 30.98%, 6.75% and 1.23%, respectively. The average IPAADP was (67.03±26.79)% and the incidence of CR was 26.99%, and the IPAADP was (31.29±12.60)%. The IPAADP of CYP2C19*2 and *3 gene carriers were decreased significantly (P0.05). There was no statistical difference in the distribution of CYP2C19 genotypes and metabolic types in NCR and CR (P>0.05). CONCLUSION: CYP2C19 genotypes have significant effect on IPAADP, but there is no association with the occurrence of CR, and the related study needs to be further verified.

The role of CYP2C19 gene assay in antiplatelet therapy after off-pump coronary artery bypass grafting / 中华胸心血管外科杂志

Objective To evaluate the guiding role of CYP2C19 gene assay in dual antiplatelet therapy(DAPT) after off-pump coronary artery bypass grafting ( OPCABG ) .Methods The patients who received scheduled OPCABG between May 2017 and May 2018 were recruited in this study.According to the results of CYP2C19 gene assay, the patients who carried CYP2C19 gene *2/*2,*2/*3 and*3/*3 mainly causing slow metabolism of clopidogrel were randomly divided into two groups: the clopidogrel group(patients receiving 100mg/qd aspirin plus 75mg/qd clopidogrel after surgery ), the ticagrelor group(patients receiving 100mg/qd aspirin plus 90mg/bid ticagrelor after surgery).Patients in the two groups underwent plate-let aggregation rate test first day before surgery and the 1, 4, 7 days antiplatelet therapy after surgery.And the major adverse cardiac events(MACE) was investigated 30 days after surgery in the two groups.Results A total of 244 patients were recrui-ted in the study with the clopidogrel group(n=122) and the ticagrelor group(n=122).The platelet aggregation rate after one day of postoperative DAPT in the ticagrelor group was lower than that in the clopidogrel group[(28.5 ±9.7)％ VS(51.8 ± 16.8)％, P<0.05].After 4 days of postoperative DAPT, platelet aggregation rate in the ticagrelor group maintained a stable and desired level.The MACE 30 days after surgery in the clopidogrel group and the ticagrelor group were 3.3％ and 1.6％ re-spectively, and ticagrelor plus aspirin reduced MACE in patients undergone coronary endarterectomy , P=0.043.Conclusion According to the results of CYP2C19 gene assay, ticagrelor replacing clopidogrel could shorten the duration of desired platelet aggregation rate in patients with DAPT after OPCABG , and may be reduce the risk of MACE after OPCABG and coronary end-arterectomy.

Correlation of CYP2C19 genotypes and Helicobacter pylori infection in children / 中华实用儿科临床杂志

Objective To evaluate CYP2C19 genotypes distribution in children with Helicobacter pylori (Hp) infection and to know its correlation with gender,age,severity and frequency of clinical symptoms,pathological classification of gastric antral mucosa.Methods Antral mucosas of 214 Hp infection patients who were hospitalized at Beijing Children's Hospital of Capital Medical University from July 2013 to December 2015 were collected.Genotypes were determined by PCR-sequence specific primer method,which were classified as homozygous extensive metabolizer (HomEM),heterozygous extensive metabolizer (HetEM) and poor metabolizer (PM).The differences in CYP2C19 genotype distribution in gender,age,severity and frequency of clinical symptoms,pathological classification of gastric antral mucosa were analyzed.Results (1) Among 214 Hp infected children,the percentage of HomEM was 48.1％ (103/214 cases),HetEM was 46.3％ (99/214 cases),and PM was 5.6％ (12/214 cases).PM in the CYP2C19 infection patients was lower than that in the normal Han nationality in China,and the difference was statistically significant (P ＜ 0.05).(2)Among the 214 Hp infected patients,there were 124 males and 90 females,and their median age was 9 years and 9 months(ranged from 2 years and 8 months to 17 years and 11 months).There was no statistical difference in gender and age of CYP2C19 genotypes(all P ＞ 0.05).(3) There was no statistical difference in severity and frequency of clinical symptoms of CYP2C19 genotypes(all P ＞0.05).(4) In HomEM group,according to pathological classification of gastric mucosa,there were 14 cases of mild injury,36 cases of moderate injury and 53 cases of severe injury,respectively.In HetEM group,there were 17 cases of mild injury,29 cases of moderate injury and 53 cases of severe injury,respectively.In PM group,there were 2 cases of mild injury,3 cases of moderate injury and 7 cases of severe injury,respectively.There was no statistical difference in the pathological degree of inflammation changes in gastric antral mucosa of CYP2C19 genotypes(all P ＞0.05).(5)Thirty-five cases didn't receive treatment,78 cases received Hp eradication one time and failed,101 cases received no less than 2 times of unsuccessful Hp eradication.The number of Hp unsuccessful eradications were positively correlated with the degree of pathological inflammation changes (r =0.219,P ＜ 0.01).There was obvious difference between the number of Hp unsuccessful eradication and the pathological degree of inflammation changes in gastric antral mucosa (x2 =12.414,P ＜ 0.05).Conclusions There was no statistical difference in CYP2C19 genotypes distribution as for different gender,age,severity and frequency of clinical symptoms,pathological classification of gastric antral mucosa and CYP2C19 genotypes.The number of Hp unsuccessful eradication was positively correlated with the degree of pathological inflammation changes.

Correlation between CYP2C19 gene polymorphism and clinical efficacy of compound danshen dropping pills in treatment of senile coronary atherosclerotic heart disease / 中国中西医结合急救杂志

Objective To study the correlation between the polymorphism of CYP2C19 gene and the clinical efficacy of compound Danshen dripping pills in treatment of senile coronary atherosclerotic heart disease (CHD) and to provide theoretical basis for rational drug use. Methods Two hundred and six elderly patients with CHD treated in the Third Hospital of Hebei Medical University from June 2015 to December 2017 were screened for genotype detection and classification. All patients were given oral compound Danshen dripping pills, 10 pills each time, 3 times a day, for consecutive 2 months. Serological indexes, electrocardiograph (ECG) monitoring, liver and kidney function testing were performed before and after treatment to evaluate drug efficacy and adverse reactions. Results In senile patients with CHD, after taking compound danshen dripping pills for 2 months, the efficacy in patients with intermediate metabolizer (IM) was more significantly effective than the efficacies of the patients with extensive metabolizer (EM) and poor metabolizer (PM) [clinical efficacy: 95.6% (87/91) vs. 80.5% (33/41), 93.2% (69/74), ECG efficacy: 95.6% (87/91) vs. 78.0% (32/41), 94.6% (70/74)], at the same time, the serum levels of triglyceride (TG) and high-density lipoprotein (HDL) in patients with IM were also higher than those in patients with PM and EM [TG (mmol/L): 1.33±0.52 vs. 1.33±0.41, 1.33±0.27, HDL (mmol/L): 1.58±1.17 vs. 1.44±0.65, 1.38±0.18], and the levels of total cholesterol (TC), low-density lipoprotein (LDL) and hypersensitive C-reactive protein (hs-CRP) were lower than those of PM and EM [TC (mmol/L): 3.48±0.25 vs. 3.56±0.96, 3.51±0.51, LDL (mmol/L): 2.19±0.35 vs. 2.23±0.49, 2.21±0.87, hs-CRP (mg/L): 3.50±1.07 vs. 3.53±1.51, 3.54±2.01]. The incidences of adverse reactions in patients with EM and IM were significantly lower than the incidence of PM [6.8% (5/74), 9.9% (9/91) vs. 31.7% (13/41)], the differences being statistically significant (both P < 0.05). Conclusions CYP2C19 gene polymorphism is closely related to C HD in elderly, in such patients with IM, after taking compound Danshen dripping pills, the efficacy is significant and has low incidence of adverse reactions. Therefore, in the course of clinical treatment of elderly patients with CHD, genetic testing should be carried out to fully consider the influence of CYP2C19 gene polymorphism on the efficacy of the pill, and adopting personalized therapy can increase efficacy and reduce toxicity.

Correlation between efficacy of Ticagrelor and CYP2C19 gene polymorphism in patients with diabetes mel-litus complicated with acute coronary syndrome receiving PCI / 实用医学杂志

Objective To study the CYP2C19 genotype in patients with acute coronary syndrome(ACS) complicated with diabetes mellitus(DM)receiving percutaneous coronary intervension(PCI)by polymerase chain reaction(PCR),and to evaluate the efficacy of Ticagrelor in CYP2C19 gene polymorphism. Methods A total of 494 ACS patients with DM were enrolled. The patients were divided into routine treatment group and individual treatment group. Routine treatment group received 0.1 g/d aspirin/d and 75 mg/d of Clopidogrel. CYP2C19 gene polymorphism was examined in individual treatment group.(*1/*1)was classified into fast metabolic type,mutant heterozygous type(*1/*2,*1/*3)into intermediate metabolic type and mutant pure type (*2/*2,*2/*3,*3/*3) into slow metabolic type. Fast metabolic type received aspirin 0.1 g/d and Clopidogrel 75 mg/d,and intermediate and slow metabolic type received aspirin 0.1 g/d and Ticagrelor 90 mg bid for 12 months or more to observe the inci-dence of adverse cardiovascular events ,bleeding and other adverse reactions in 2 groups. Results The incidence of cardiac death ,recurrent myocardial infarction and angina pectoris ,stroke ,stent thrombosis and target vessel revascularization in routine treatment group was significantly higher than that in individual treatment group(P <0.05). There was no significant difference between two groups in terms of major bleeding and secondary bleeding (P > 0.05). The minimum bleeding rate was slightly higher in intermediate metabolic type in individual treatment group but without significantly difference when compared with that in fast metabolic type and slow metabolic type (both P>0.05). Conclusion Without elevating the risk of bleeding within 12 months,the efficacy of Ticagrelor is not affected by CYP2C19 gene polymorphism in patients with ACS complicated with DM after PCI.

Study on the related factors with clopidogrel resistance of patients with acute cerebral infarction / 中国综合临床

Objective To study the effect of clopidogrel on different CYP2C19 genotypes and platelet reactivity in acute cerebral infarction patients with antiplatelet aggregation.Methods Four hundred and seventy-four cases of cerebral infarction patients in Beijing Tiantan Hospital Affiliated to Capital Medical University from April 2015 to April 2016 were collected.CYP2C19 genotype was determined,and the genotype was divided into the wild type group,the heterozygous type group and the mutant homozygous group.Platelet aggregation inhibition rate(ADP%) and platelet reactivity index induced by ADP were detected.Patients were divided into clopidogrel resistance group(group CR) and non resistant group according to whether ADP% was less than 30.SPSS 16.0 statistical software was used for statistical analysis,the comparison between groups using independent samples t test,chi square test and multivariate analysis using Logistic regression analysis,when P<0.05 difference was statistically significant.Results Among the 474 patients,204 cases(43.04%) were divided into wild-type group,and 204(43.04%) and 66(13.92%) were divided into the mutant heterozygous group and mutant homozygous group.In Chi square test analysis,clopidogrel resistance group and non resistance group CYP2C19 genotype distribution was significantly different(χ2=6.658,P=0.036).CR group angle(α) values((68.87±5.47)°) and MA((66.77±6.25) mm) were higher than that of CS group ((66.55±6.05)° and (63.30±5.66) mm,t=2.199,3.387,P=0.029,0.001).The multivariate logistic regression analysis showed that OR of angle level was 1.028,95%CI was 0.929-1.137 (P=0.595);OR of Ma level was 1.561,95%CI was 0.785-0.970 (P=0.012).Conclusion The effect of clopidogrel on platelet aggregation in patients with acute cerebral infarction is decreased by CYP2C19 gene mutation.CYP2C19 mutant allele is a risk factor for clopidogrel resistance.Angle (α) value and MA value are the risk factors for the diagnosis of CR in the patients with acute cerebral infarction,and the risk of clopidogrel resistance increased when the patients′ Angle (α) value and the value of MA increased.MA value as a predictor of CR and the screening tool has a certain value.

Pharmacoeconomics Evaluation of CYP2C19 Genetic Test Guiding Antiplatelet Therapy for Acute Coro-nary Syndrome Patients in China / 中国药房

OBJECTIVE:To evaluate the feasibility of using CYP2C19 gene to guide the use of antiplatelet agents in acute cor-onary syndrome(ACS)patients undergoing interventional operation in China from the viewpoint of pharmacoeconomics. METH-ODS:Based on global PLATO trial data,the patients were divided into 3 groups according to treatment strategies(clopidogrel group,ticagrelor group,genetic test group). By applying Treeage Pro 2011 software,short-term decision tree model and long-term Markov model were established,and related data were imported to evaluate cost-effectiveness of different treatment strategies. RE-SULTS&CONCLUSIONS:For ACS patients,according to the level of GDP in China,conventional use of ticagrelor is of pharma-coeconomic advantage for in Shanghai and uninsured patients insured patients;the use of antiplatelet agents guided by CYP2C19 gene test is of pharmacoeconomic advantage among nationwide insured patients.

Study on the Correlation of Gene Polymorphism with Antiplatelet Efficacy of Clopidogrel in PAD Patients / 中国药房

OBJECTIVE:To investigate the correlation of gene polymorphism in peripheral artery disease(PAD)patients with antiplatelet efficacy of clopidogrel. METHODS:Reviewing related domestic and foreign literatures in recent years,the correlation of gene polymorphism in PAD patients with antiplatelet efficacy of clopidogrel was summarized and analyzed. RESULTS&CON-CLUSIONS:At present,a variety of genes associated with clopidogrel antiplatelet efficacy and major adverse cardiovascular events (MACE)have been identified,including cytochrome P450(CYP)2C19,adenosine three phosphate binding cassette B subfamily 1 (ABCB1),paraoxonase 1 (PON1) and adenosine diphosphate P2Y12 receptor (P2Y12),etc. CYP2C19*2,*3 allele may reduce the antiplatelet effect of clopidogrel. Their correlation has been confirmed by a number of studies,and study results are broadly con-sistent. Mutations in the ABCB1 C3435T and PON1 Q192R sites may lead to a lower response to clopidogrel and increase the risk of MACE;but there is a lack of large-scale prospective clinical studies,and the present results are inconsistent. P2Y12 gene poly-morphism in PAD patients has not been found to be significantly associated with clopidogrel efficacy.

Research on correlation between CYP2C19 gene polymorphism and clopidogrel curative effect in patients with coronary heart disease / 国际检验医学杂志

Objective To analyze and investigate the correlation between the CYP2C19 gene polymorphism and clopidogrel cura-tive effect in the patients with coronary heart disease (CHD) to provide valuable reference information for the future clinical work. Methods A total of 128 cases of CHD undergoing PCI in our hospital from January 2015 to January 2016 were selected as the re-search subjects.All of them were treated with clopidogrel ,the loading dose was 300mg ,and the maintenance dose was 75mg.The subjects were divided into the clopidogrel resistance group and response group.The drug-metabolizing CYP2C19 genotype was com-pared between the two groups and the effect of CYP2C19 genotype on the clopidogrel response was observed.Results Among the subjects ,27 cases were clopidogrel resistance.A total of 16 cases of CYP2C19 slow metabolic gene carriers were detected.There was statistically significant difference between the patients with chronic metabolic genotype VASP-PRI with fast metabolic geno-type and intermediate metabolic genotype(P<0.05).The incidence rate of adverse end point events had statistical difference be-tween the clopidogrel resistance group and clopidogrel response group(P<0.05).Conclusion In the risk factors of clopidogrel re-sistance ,slow metabolism CYP2C19 genotype and clopidogrel resistance will increase the risk of clinical adverse endpoint events oc-currence ,clinic should give adequate attention.

Individualized Antiplatelet Therapy Analysis and Pharmaceutical Care for a Patient with Subacute Stent Thrombosis after PCI / 中国药房

OBJECTIVE:To investigate the role of clinical pharmacists in individualized antiplatelet therapy for a patient with subacute stent thrombosis after PCI.METHODS:Clinical pharmacists participated in the therapy for a myocardial infarction patient with diabetes,and the patient suffered from subacute stent thrombosis at the fourth day after PCI.Clinical pharmacists suggested performing clopidogrel-related gene detection [Cytochrome P450(CYP)2C19] through comprehensively analyzing the complexity of the lesion,the time of stent thrombosis,the number of stent implantations and combined diseases,etc.According to detection result (CYP2C19* 1/*2),clinical pharmacists suggested to additionally use Cilostazol tablets 50 mg,po,bid,on the basis of previous dual antiplatelet therapy;additionally use Alprostadil injection 10 μg,ivgtt,qd to improve microcirculation.Pharmaceutical care as therapeutic evaluation,ADR monitoring were performed,and medication education as medication notes and dietary adjustments were also provided.RESULTS:Physicians adopted the suggestions of clinical pharmacists;the patient was recovered and discharged from hospital.After discharge,the disease condition kept stable due to persistent aspirin+clopidogrel+cilostazol triple antiplatelet therapy.CONCLUSIONS:Drug metabolizing enzyme is an important cause of individual differences in antiplatelet effects and toxicity,and its gene polymorphism is closely related with clinical outcome and terminal event.Clinical pharmacists should play professional skill to assist physician to access and interpret relevant information,and formulate and adjust individualized antiplatelet therapy after considering disease condition,combined diseases and genotypes,so as to guarantee safe and effective drug use.

Relationship between Clopidogrel Response ,Early Neurological Deterioration and CYP2C19 Gene Polymorphism in Symptomatic Intracranial Atherosclerotic Stenosis (sICAS)Patients / 中山大学学报(医学科学版)

[Objective]To investigate the relationship between clopidogrel response , early neurological deterioration and CYP2C19 gene polymorphism in sICAS patients.[Methods]116 sICAS patients were divided into deterioration group and non-deterio?ration group by whether appear early nervous function deterioration. Record included the baseline data,the genotypes of CYP2C19, platelet maximum aggregation rate after 7 days of given clopidogrel,CYP2C19 genotype and clopidogrel reaction were compared be?tween two groups.[Results]The deterioration group combination with diabetes ,stroke/TIA were significantly higher than the non-de?terioration group(P<0.05);The frequency of CYP2C19*2 AA genotype and A allele were significantly higher than those in non-dete?rioration group. The frequency of GG genotype were significantly lower than non-deterioration group (27.27% vs 2.13%,50.00% vs 14.84%,27.27% vs 72.34%)(P<0.01);The poor metabolic genotype platelet maximum aggregation rate were significantly higher than that of the fast-metabolic genotype and middle metabolic genotype(P<0.01,P<0.05),Middle metabolic genotype platelet maxi?mum aggregation rate were significantly higher than fast-metabolic genotype(P<0.01);The deterioration group fast-metabolic geno?type were significantly lower than non-deterioration group ,poor metabolic genotype were significantly higher than non-deterioration group(22.73% vs 65.96%,36.36% vs 5.32%)(P<0.01);Clopidogrel resistance rate 59.09% were significantly higher non-deteriora?tion group 28.72%(P<0.05).[Conclusion]Clopidogrel response and early neurological deterioration in sICAS patients is associatedwith CYP2C19 gene polymorphism.

Correlation between efficacy of Ticagrelor and CYP2C19 gene polymorphism in patients with diabetes mel-litus complicated with acute coronary syndrome receiving PCI / 实用医学杂志

Objective To study the CYP2C19 genotype in patients with acute coronary syndrome(ACS) complicated with diabetes mellitus(DM)receiving percutaneous coronary intervension(PCI)by polymerase chain reaction(PCR),and to evaluate the efficacy of Ticagrelor in CYP2C19 gene polymorphism. Methods A total of 494 ACS patients with DM were enrolled. The patients were divided into routine treatment group and individual treatment group. Routine treatment group received 0.1 g/d aspirin/d and 75 mg/d of Clopidogrel. CYP2C19 gene polymorphism was examined in individual treatment group.(*1/*1)was classified into fast metabolic type,mutant heterozygous type(*1/*2,*1/*3)into intermediate metabolic type and mutant pure type (*2/*2,*2/*3,*3/*3) into slow metabolic type. Fast metabolic type received aspirin 0.1 g/d and Clopidogrel 75 mg/d,and intermediate and slow metabolic type received aspirin 0.1 g/d and Ticagrelor 90 mg bid for 12 months or more to observe the inci-dence of adverse cardiovascular events ,bleeding and other adverse reactions in 2 groups. Results The incidence of cardiac death ,recurrent myocardial infarction and angina pectoris ,stroke ,stent thrombosis and target vessel revascularization in routine treatment group was significantly higher than that in individual treatment group(P <0.05). There was no significant difference between two groups in terms of major bleeding and secondary bleeding (P > 0.05). The minimum bleeding rate was slightly higher in intermediate metabolic type in individual treatment group but without significantly difference when compared with that in fast metabolic type and slow metabolic type (both P>0.05). Conclusion Without elevating the risk of bleeding within 12 months,the efficacy of Ticagrelor is not affected by CYP2C19 gene polymorphism in patients with ACS complicated with DM after PCI.

Optimizing Two Antiplatelet Regimens Based on the CYP2C19 Gene Detection / 医药导报

Objective To select antiplatelet regimen according to the results of CYP2C19 gene polymorphism,and then compare the major adverse cardiac events,bleeding events and the incidence of adverse reactions between two antiplatelet regimens. Methods Two hundred and seven patients who were diagnosed with acute coronary syndrome(ACS)and underwent elective PCI were tested for CYP2C19 genetic polymorphism,and 94 cases with CYP2C19 intermediate metabolism were randomly divided into high-dose clopidogrel group and ticagrelor group(47 cases each).High-dose clopidogrel group was given clopidogrel 150 mg once daily,and ticagrelor group ticagrelor 180 mg twice daily.Major adverse cardiac events,bleeding events and the incidence of adverse reactions were observed between two groups one month later. Results The average declined platelet aggregation rate was significantly different between the two groups[(6.27±5.65)% and(12.30±10.23)%,P<0.01];Adverse drug reactions ,the incidence of bleeding events and major adverse cardiac events of two groups were not significantly different. Conclusion Ticagrelor has stronger antiplatelet aggregation effects than high-dose clopidogrel.There is no difference in short-term clinical outcomes between the two groups.

Analysis of the Polymorphism Distribution of Clopidogrel Metabolism Related Gene CYP2C19 in Patients with Coronary Artery Disease in Wuhan / 现代检验医学杂志

Objective To screen for clopidogrel metabolism related gene CYP2C19 in patients with coronary artery disease in Wuhan.Methods 316 patients,from Jan to Dec 2014,after cardiology percutaneous coronary interventional therapy (PCI) for the treatment of coronary artery disease were selected as research object.Clopidogrel metabolism related CYP2C19 geno-types (* 1,* 2,* 3)were detected by the gene chip,and for different types of metabolism of patients according to CYP2C19 gene type:strong metabolize type (*1/*1),intermediate metabolizer types (*1/*2,*1/*3),poor metaboli-zer types (*2/*2,*3/*3,*2/*3).Results According to the CYP2C19 gene polymorphism of metabolic function type, strong metabolic type carrying CYP2C19*1 (*1/*1)accounted was 43.4%,intermediate metabolizers carrying CYP2C19*2 or *3 (* 1/* 2 and * 1/* 3)and poor metabolizers (* 2/* 2,* 2/* 3 and * 3/* 3)accounted was 42.4% and 14.2%,respectively.Different gender had no statistical significance in CYP2C19 genotype differences.Conclusion Clopi-dogrel metabolism functional of CYP2C19 gene in patients with interventional coronary heart disease in Wuhan area had more deletion gene.

Clinical Value of CYP2C19 Polymorphisms for Guiding the Anti-platelet Therapy in CAD patients After Percutaneous Coronary Intervention / 中国循环杂志

Objective: To explore the value of CYP2C19 genotype polymorphisms for guiding the strategy of anti-platelet therapy in coronary artery disease (CAD) patients after percutaneous coronary intervention (PCI) with clinical prognosis. Methods: A total of 326 CAD patients with PCI treatment received CYP2C19 genotype examination. According to CYP2C19 polymorphisms, the patients were divided into 3 groups. The patients with CYP2C19*1/*1, fast metabolism were defined as Routine group, who received clopidogrel 75 mg/day,n=128. The patients with CYP2C19*1/*2, CYP2C19*1/*3, CYP2C19*2/*3, CYP2C19*2/*2, CYP2C19*3/*3, medium and slow metabolism were further divided into 2 groups as High clopidogrel group, who received clopidogrel 150 mg/day,n=99 and Ticagrelor group, who received ticagrelor 90 mg/bid,n=99. The changes of platelet aggregation rate (PAgT) at before and 1, 3, 6 months after PCI were observed, the major adverse cardiac events (MACE) and bleeding condition were compared among different groups at 6 months after PCI. Results: The PAgT was similar between High clopidogrel group and Routine group at 1, 3, 6 months after PCI, P>0.05;while compared with High clopidogrel group and Routine group, the PAgT decreased in Ticagrelor group at 1, 3, 6 months after PCI,P0.05; while compared with High clopidogrel group and Routine group, Ticagrelor group had much less MACE occurrence,P0.05. Conclusion: High dose clopidogrel does not increase MACE occurrence in CAD patients with CYP2C19 medium and slow metabolism after PCI. Ticagrelor may decrease PAgT and MACE occurrence without elevating the major bleeding events.

Relation between CYP2C19 phenotype and genotype in a group of Brazilian volunteers / Relação entre genótipo e fenótipo de CYP2C19 em um grupo de voluntários brasileiros

The CYP2C19 gene presents polymorphism affecting the pharmacokinetics of several drugs of clinical importance. The purpose of this study was to investigate the correlation between CYP2C19 genotype and metabolic phenotype in a group of 38 Brazilian volunteers, evaluating the phenotype prediction capacity of the genotyping procedure. For CYP2C19 phenotyping, omeprazole was used as the probe drug, using the hydroxylation metabolic ratio as the phenotypic indicator. Venous blood samples were drawn before and three hours after an oral administration of 20 mg omeprazole. The plasma concentrations of omeprazole and hydroxy-omeprazole were determined by high performance liquid chromatography. The genotyping assay was carried out using a Real-Time-PCR-based assay, identifying the alleles *1 (completely functional), *2, *3 and *4 (null). The phenotyping procedure estimated the presence of 4 poor, 34 extensive and 1 ultra-extensive metabolizer. The genotyping identified 4 poor, 23 extensive and 11 intensive metabolizers. The groups of volunteers classified according to the number of active alleles of CYP2C19 had significant differences in the metabolic ratios of omeprazole hydroxylation. However, volunteers exhibiting the same number of active alleles presented different phenotypes. Therefore, the phenotyping of CYP2C19 is a more promising alternative to dose individualization of CYP2C19 substrate drugs.

O gene CYP2C19 apresenta polimorfismo genético, com impacto importante na farmacocinética de diversos fármacos de importância clínica. O objetivo deste estudo foi avaliar a correlação entre genótipo e fenótipo de CYP2C19 em um grupo de 38 voluntários brasileiros, avaliando a capacidade de predição do fenótipo a partir de testes de genotipagem. Para a fenotipagem, utilizou-se omeprazol (OME) como fármaco-sonda para CYP2C19, empregando sua razão metabólica de hidroxilação como indicador fenotípico. Amostras de sangue foram coletadas antes e três horas após a administração oral de 20mg do fármaco. As concentrações plasmáticas de OME e seu metabólito foram determinadas por cromatografia líquida de alta eficiência. A genotipagem de CYP2C19 foi realizada através de ensaio baseado na reação em cadeia da polimerase em tempo real, identificando os alelos *1 (completamente funcional),*2 e *3 (nulos). Pela fenotipagem foi possível estimar a presença de 3 metabolizadores lentos, 34 rápidos e 1 ultra-rápido; enquanto pela genotipagem foi determinada a presença de 4 metabolizadores lentos, 23 rápidos e 11 intermediários. Os grupos de voluntários classificados de acordo com o número de alelos ativos apresentaram diferenças significativas entre as razões metabólicas de hidroxilação de omeprazol. Entretanto, indivíduos com o mesmo genótipo apresentaram fenótipos diferentes. Desta forma, a fenotipagem apresenta-se como alternativa mais promissora para a individualização das doses de fármacos substratos de CYP2C19.