Comparison of mechanism-based inhibition of human cytochrome P450 2C19 by ticlopidine,clopidogrel, and prasugrel

1. Mechanism-based inhibition of CYP2C19 in human liver microsomes by the thienopyridine antiplatelet agents clopidogrel, prasugrel and their thiolactone metabolites was investigated by determining the time- and concentration-dependent inhibition of the activity of S-mephenytoin 4′-hydroxylase as typical CYP2C19 activity and compared with ticlopidine and its metabolite.

2. Clopidogrel was shown to be a mechanism-based inhibitor of CYP2C19 with the inactivation kinetic parameters, k_inact and K_I, equal to 0.0557?min^?1 and 14.3?μM, respectively, as well as ticlopidine (0.0739?min^?1 and 3.32?μM, respectively). The thiolactone metabolite of ticlopidine and clopidogrel inhibited CYP2C19 only in a concentration-dependent manner. In contrast, neither prasugrel nor its thiolactone metabolite inhibited CYP2C19 at concentrations up to 100?μM.

3. The oxidation of the thiophene moiety of clopidogrel to form their respective thiolactones was found to be the critical reaction that produces the chemically reactive metabolites which cause the mechanism-based inhibition of CYP2C19.

4. Estimation of in vivo drug–drug interaction using in vitro parameters predicted clinically observed data. For clopidogrel, there was no increase in the area under the curve (AUC) at its clinical dose level as predicted by the in vitro parameters, and for ticlopidine the prediction agreed with the clinically observed AUC increase.

5. In conclusion, clopidogrel is potent mechanism-based inhibitors of CYP2C19 as well as ticlopidine, whereas prasugrel did not inactivate CYP2C19. Administration of prasugrel would not cause a clinically relevant interaction with CYP2C19.

     

Impaired liver cytochrome P450 2C11 activity after dual antiplatelet therapy with aspirin and clopidogrel in rats

1. Aspirin (ASA) and clopidogrel (CLP) are used in combination as dual antiplatelet therapy (DAPT) for acute coronary syndrome based on their complementary mechanisms for platelet aggregation inhibition. However, the pharmacokinetics of such drug combination usage has not been thoroughly investigated.

2. In the current study, an LC–MS/MS method was developed to simultaneously determine the plasma concentrations of ASA and its metabolite salicylic acid (SA) with CLP and its metabolites, clopidogrel carboxylic acid (CLPM) and clopidogrel active metabolite derivative (CAMD). The pharmacokinetics of ASA, SA, CLP, CLPM and CAMD in rats receiving two-week DAPT with ASA and CLP were then determined.

3. After two-week DAPT with ASA and CLP in rats, the activities of aspirin esterase and rCyp2c11, enzymes mediating rat metabolism of ASA and CLP, respectively, in prepared rat liver microsomes were measured followed by further determination of rCyp2c11 mRNA expressions. The results demonstrated that DAPT led to minimal impact on aspirin esterase activity but significant decrease in rCyp2c11 activity and mRNA expression.

4. In conclusion, our findings on impairment in rCyp2C11 activity and mRNA expression by DAPT in rats could provide guidance on its safe clinical use with other CYP 2C19 substrates.     

替格瑞洛与氯吡格雷在CYP2C19等位基因功能缺失患者中的抗血小板疗效比较

目的比较替格瑞洛与氯吡格雷在细胞色素P450 C19(CYP2C19)等位基因功能缺失的行冠状动脉介入治疗(PCI)的急性冠状动脉综合征(ACS)患者中应用的抗血小板疗效。方法选取行PCI的ACS患者,筛选CYP2C19等位基因功能缺失患者,包括*2/*2、*2/*3以及*3/*3。共入选患者52例,随机分为两组,每组26例。替格瑞洛组于PCI术前给予替格瑞洛180 mg负荷量后90 mg,po,bid;氯吡格雷组术前给予氯吡格雷300 mg负荷量后75 mg,po,qd。若是急诊PCI手术,替格瑞洛组于术前给予替格瑞洛180 mg负荷量后90 mg,po,bid;氯吡格雷组术前给予氯吡格雷600 mg负荷量后75 mg,po,qd维持。观察患者术后1年的主要心脑血管不良事件(MACCE)、出血情况及其他药物不良反应。结果两组患者基线资料无显著差异(P>0.05),应用血管紧张素转换酶抑制药/血管紧张素受体拮抗药、肾上腺素β受体阻滞药比例无显著差异(P>0.05)。术后1年,替格瑞洛组MACCE发生率为8%(2/26),低于氯吡格雷组(31%,8/26,P<0.05)。两组出血事件发生率分别为12%和8%,组间差异无显著意义(P>0.05)。结论 CYP2C19等位基因功能缺失患者给予替格瑞洛治疗可改善临床预后,基于CYP2C19基因型的个体化方案可考虑在行PCI术的ACS患者中实施。     

Gene polymorphism of cytochrome P450 2C19*2 and clopidogrel resistance reflected by platelet function assays: a meta-analysis

Background

The relationship between CYP2C19*2 gene polymorphism and clopidogrel resistance reflected by platelet function assays has been studied extensively in the past several years, while no clear conclusion can be drawn from the previous studies. To explore a more precise estimation of the relationship, a meta-analysis was conducted in the present study.

Methods

The relevant studies were identified by searching PubMed, EMBASE, the Web of Science, Cochrane Collaboration Database, Chinese National Knowledge Infrastructure (CNKI), Wanfang Database, and China Biological Medicine (CBM) up to February, 2014. The meta-analysis was performed by the STATA 11.

Results

Eight studies with a total of 2,331 subjects, including 1,066 patients with clopidogrel resistance and 1,265 patients without clopidogrel resistance were included. The pooled analysis showed that CYP2C19*2 gene polymorphism was probably associated with clopidogrel resistance (OR (95 % CI): GA vs. GG: 2.10 (1.74–2.53); AA vs. GG: 3.05 (2.10–4.45); dominant model: 2.22 (1.85–2.65); recessive model: 2.33 (1.62–3.36)). No statistically significant difference was found in the analysis of the three subgroups. The statistical stability and reliability was also demonstrated by the sensitivity analysis and publication bias outcomes.

Conclusion

The meta-analysis suggests that CYP2C19*2 gene polymorphism may be associated with clopidogrel resistance.     

A discordance of the cytochrome P450 2C19 genotype and phenotype in patients with advanced cancer

AIMS: To examine the relationship between cytochrome P450 2C19 (CYP2C19) genotype and expressed metabolic activity in 16 patients with advanced metastatic cancer. METHODS: Individual CYP2C19 genotypes were determined by PCR-based amplification, followed by restriction fragment length analysis, and compared with observed CYP2C19 metabolic activity, as determined using the log hydroxylation index of omeprazole. RESULTS: All 16 patients had an extensive metabolizer genotype. However, based on the antimode in a distribution of log omeprazole hydroxylation indices from healthy volunteers, four of the patients had a poor metabolizer phenotype and there was a general shift of the remaining 12 patients towards a slower metabolic phenotype. This suggests a reduction in metabolic activity for all patients relative to healthy volunteers. A careful analysis of patient medical records failed to reveal any drug interactions or other source for the observed discordance between genotype and phenotype. CONCLUSIONS: There are no previous reports of a 'discordance' between genotype and expressed enzyme activity in cancer patients. Such a decrease in enzyme activity could have an impact on the efficacy and toxicity of chemotherapeutic agents and other drugs, used in standard oncology practice.     

Metabolic ratios of psychotropics as indication of cytochrome P450 2D6/2C19 genotype

The cytochrome P450 enzymes (CYP) 2C19 and 2D6 are involved in the metabolism of many psychotropic drugs. Variability in enzyme activity results in variable metabolic capacities, affecting the metabolism of substrates. The metabolic ratio (MR) of drugs metabolized via these enzymes may therefore reflect the enzyme's activity and/or genotype. To serve as an example for different groups of medications, the selective serotonin reuptake inhibitor venlafaxine, the tricyclic antidepressant amitriptyline, and the antipsychotic risperidone were studied to examine a possible correlation between the MRs of these drugs and the CYP2C19 and/or CYP2D6 genotype. For this purpose data from routine genotyping and serum level analysis were used. The relationships between the observed metabolic ratios and CYP2D6 and/or CYP2C19 genotype were characterized using nonparametric statistical analysis. A clear correlation was observed between the CYP2D6 genotype and the metabolic ratio of venlafaxine. Genotyping of individuals with a log(MR) < -0.6 or a log(MR) > 0.2 would include all patients with an aberrant genotype but would result in a reduction of 52% of genotyping reactions. Slow metabolism of amitriptyline is correlated with a log(MR) > 0.4. Genotyping only those subjects with a log(MR) > 0.4 would result in 88% fewer genotyping reactions. For risperidone, genotyping individuals with a log(MR) > 0.4 would include all CYP2D6 poor metabolizers while reducing the number of genotyping reactions by 93%. According to these data, correlations exist between the log(MR) of venlafaxine, amitriptyline, and risperidone and the genotype of the CYP enzymes involved in their metabolism. From the ranges of log(MR) defined here, a high percentage of aberrant metabolizers can be detected even when patients are not routinely genotyped. Thus, the metabolic ratio may serve as an indication of when genotyping should be considered.     

Lornoxicam pharmacokinetics in relation to cytochrome P450 2C9 genotype

AIMS: To investigate the pharmacokinetics of lornoxicam and the relationship with CYP2C9 polymorphism in healthy Chinese subjects. METHODS: A single oral dose of 8 mg lornoxicam was administered to 18 healthy Chinese male subjects. Plasma was sampled for 24 h post dose, and plasma concentrations of lornoxicam were measured using a validated LC/MS/MS method. CYP2C9 genotype was determined by polymerase chain reaction-based restriction fragment length polymorphism or by direct sequencing of the coding region of the CYP2C9 gene. RESULTS: Of the 18 subjects, one subject was found to be a very poor metabolizer of lornoxicam with a long t(1/2) of 106 h, a low CL/F of 0.71 ml min(-1), and a high AUC(0-infinity) of 187.6 microg ml(-1) h. Genotyping studies revealed that this subject was heterozygous for CYP2C9*3 and a new variant CYP2C9 allele. Of the other 17 subjects, 13 were *1/*1 carriers, three were *1/*3 carriers, and one was a *1/*2 carrier. Mean AUC(0-infinity) values (95% confidence intervals) of lornoxicam were 9.25 (6.55, 11.95) vs. 4.75 (3.55, 5.95) microg ml(-1) h in *1 heterozygotes vs.*1 homozygotes, and mean CL/F values were 14.8 (10.2, 19.4) vs. 32.9 (24.5, 41.3) ml min(-1), respectively (P < 0.05 for both AUC and CL/F). CONCLUSIONS: The results show that the pharmacokinetics of lornoxicam are dependent on CYP2C9 polymorphism. In particular, the presence of the CYP2C9*3 allele impairs the oral clearance of lornoxicam.     

Is cytochrome P450 2C9 genotype associated with NSAID gastric ulceration?

AIMS: The aim of this study was to explore whether genetic variation of cytochrome P450 2C9 (CYP2C9) contributes to NSAID-associated gastric ulceration. The hypothesis tested was that CYP2C9 poor metabolizer genotype would predict higher risk of gastric ulceration in patients on NSAIDs that are metabolized by CYP2C9, due to higher plasma NSAID concentrations. METHODS: Peripheral blood DNA samples from 23 people with a history of gastric ulceration attributed to NSAIDs metabolized by CYP2C9, and from 32 people on NSAIDs without gastropathy, were analysed to determine CYP2C9 genotype. RESULTS: The following genotypes were found: *1/*1 (wild type) in 70% of cases and 58% of controls, *1/*2 in 17% of cases and 29% of controls, *1/*3 in 13% of cases and 13% of controls. The difference between case and control nonwild-type genotype frequency was 11.5% (95% CI -14,37%), with the direction of the difference being against the hypothesis. No individuals with homozygote poor metaboliser genotype were identified. The differences in genotype frequencies between the two groups were not significant and the frequencies were similar to those in a large published population study. Ninety-five percent binomial confidence interval analysis confirms that there is no apparent clinically significant relationship between CYP2C9 genotype and risk of gastric ulceration although a small difference in risk in poor metabolizers cannot be excluded. CONCLUSIONS: These results do not support the hypothesis that gastric ulceration resulting from NSAID usage is linked to the poor metabolizing genotypes of CYP2C9.     

Effect of cytochrome P450 2C19 genotype on voriconazole exposure in cystic fibrosis lung transplant patients

Purpose

Voriconazole is widely used to treat invasive aspergillosis after lung transplantation. In cystic fibrosis patients, the interindividual variability in drug disposition complicates the optimal voriconazole dosing and increases the risk of toxicity. The objective of this retrospective study was to evaluate the influence of CYP2C19 genotype on voriconazole response in lung transplant patients with cystic fibrosis.

Methods

We retrospectively studied 24 Caucasian cystic fibrosis lung transplant recipients who received voriconazole. We analyzed the influence of CYP2C19 genotype (*2 and *17 alleles) on voriconazole exposure and maintenance dose and side effects.

Results

Heterozygous carriers of the CYP2C19*2-deficient allele required lower maintenance doses (440?±?107?mg/day) compared with wild-type and CYP2C19*17-allele carriers (633?±?197?mg/day and 600?±?193?mg/day, respectively, P?CYP2C19*2 group (31.3% vs. 12.1% and 9.8% of above-range levels in the CYP2C19*1 and CYP2C19*17 groups, respectively) or CYP2C19*17 group (37.9% vs. 15.6% and 13% of below-range levels in the CYP2C19*1 and CYP2C19*2 groups, respectively) (P?CYP2C19 status.

Conclusions

In this frail population, voriconazole exposure is strongly influenced by CYP2C19 genotype, and determining the genotype before voriconazole initiation may help determine the initial dosing regimen that will promptly achieve therapeutic plasma levels without producing out-of-range levels.     

CYP2C19基因多态性对氯吡格雷抗血小板治疗疗效的影响

目的：探讨CYP2C19基因分型对急性冠状动脉综合征（ACS）患者使用氯吡格雷抗血小板的疗效。方法：对某院收治的ACS患者350例,入院时即检测CYP2C19的基因多态性及血小板聚集率,给予负荷量阿司匹林300 mg、氯吡格雷300 mg。之后常规给予患者阿司匹林100 mg·d^-1、氯吡格雷75 mg·d^-1,服用1年。根据基因型将患者分为快代谢型（n=140）、中等代谢型（n=161）和慢代谢型（n=49）。治疗后第7天第2次检测血小板聚集率。采用比浊法检测5 μmol·L^-1二磷酸腺苷诱导的血小板聚集率。对所有患者进行为期1年的随访,比较不同代谢类型患者严重心脏事件和联合心脏事件的发生率。结果：快代谢性CYP2C19*1/*1共140例,占40.0%;中等代谢型CYP2C19*1/*2 146例（41.7%）、CYP2C19*1/*3 15例（4.3%）;慢代谢型CYP2C19*2/*2 35例（10.0%）、CYP2C19*2/*3 14例（4.0%）、CYP2C19*3/*3 0例。服药7 d后,3组血小板最大聚集率均明显下降（P<0.05）。中等代谢型组最大血小板聚集率较快代谢型组高,差异有显著性（P<0.05）。慢代谢型组最大血小板聚集率均较快代谢型组和中等代谢型组高,差异有显著性（P<0.05）。不同代谢类型患者严重心脏事件发生率的比较无显著差异（P>0.05）,慢代谢型患者联合心脏事件的发生率高于快代谢型和中等代谢型患者（P<0.05）。结论：通过研究氯吡格雷对不同CYP2C19分型患者的抗血小板疗效,推荐对ACS患者在使用抗血小板药物时应进行基因多态性和血小板聚集率检测,及时调整抗血小板治疗方案,以预防不良心血管事件的发生。     

Clinical significance of the cytochrome P450 2C19 genetic polymorphism

Cytochrome P450 2C19 (CYP2C19) is the main (or partial) cause for large differences in the pharmacokinetics of a number of clinically important drugs. On the basis of their ability to metabolise (S)-mephenytoin or other CYP2C19 substrates, individuals can be classified as extensive metabolisers (EMs) or poor metabolisers (PMs). Eight variant alleles (CYP2C19*2 to CYP2C19*8) that predict PMs have been identified. The distribution of EM and PM genotypes and phenotypes shows wide interethnic differences. Nongenetic factors such as enzyme inhibition and induction, old age and liver cirrhosis can also modulate CYP2C19 activity. In EMs, approximately 80% of doses of the proton pump inhibitors (PPIs) omeprazole, lansoprazole and pantoprazole seem to be cleared by CYP2C19, whereas CYP3A is more important in PMs. Five-fold higher exposure to these drugs is observed in PMs than in EMs of CYP2C19, and further increases occur during inhibition of CYP3A-catalysed alternative metabolic pathways in PMs. As a result, PMs of CYP2C19 experience more effective acid suppression and better healing of duodenal and gastric ulcers during treatment with omeprazole and lansoprazole compared with EMs. The pharmacoeconomic value of CYP2C19 genotyping remains unclear. Our calculations suggest that genotyping for CYP2C19 could save approximately 5000 US dollars for every 100 Asians tested, but none for Caucasian patients. Nevertheless, genotyping for the common alleles of CYP2C19 before initiating PPIs for the treatment of reflux disease and H. pylori infection is a cost effective tool to determine appropriate duration of treatment and dosage regimens. Altered CYP2C19 activity does not seem to increase the risk for adverse drug reactions/interactions of PPIs. Phenytoin plasma concentrations and toxicity have been shown to increase in patients taking inhibitors of CYP2C19 or who have variant alleles and, because of its narrow therapeutic range, genotyping of CYP2C19 in addition to CYP2C9 may be needed to optimise the dosage of phenytoin. Increased risk of toxicity of tricyclic antidepressants is likely in patients whose CYP2C19 and/or CYP2D6 activities are diminished. CYP2C19 is a major enzyme in proguanil activation to cycloguanil, but there are no clinical data that suggest that PMs of CYP2C19 are at a greater risk for failure of malaria prophylaxis or treatment. Diazepam clearance is clearly diminished in PMs or when inhibitors of CYP2C19 are coprescribed, but the clinical consequences are generally minimal. Finally, many studies have attempted to identify relationships between CYP2C19 genotype and phenotype and susceptibility to xenobiotic-induced disease, but none of these are compelling.     

The effect of aging on the relationship between the cytochrome P450 2C19 genotype and omeprazole pharmacokinetics

BACKGROUND AND OBJECTIVE: The metabolic activity of cytochrome P450 (CYP) 2C19 is genetically determined, and the pharmacokinetics of omeprazole, a substrate for CYP2C19, are dependent on the CYP2C19 genotype. However, a discrepancy between the CYP2C19 genotype and omeprazole pharmacokinetics was reported in patients with liver disease or advanced cancer. The objective of the present study was to evaluate the effect of aging on the relationship between the CYP2C19 genotype and its phenotype. METHODS: Twenty-eight elderly and 23 young Japanese volunteers were enrolled after being genotyped. Each subject received a single intravenous dose of omeprazole (10 mg and 20 mg for the elderly and the young groups, respectively) and blood samples were obtained up to 6 hours after dose administration to determine the plasma concentrations of omeprazole and its metabolites, 5-hydroxyomeprazole and omeprazole sulfone. Pharmacokinetic parameters were obtained by noncompartmental analysis. Linear regression models were used to examine the joint effects of covariates such as genotype, age, etc., on the pharmacokinetic parameters, and the pharmacokinetic parameters showing statistical significance were compared by ANOVA. RESULTS: There were significant differences between genotypes in the area under the plasma concentration-time curve of the young group and the elderly group. The number of mutation alleles and age were significant covariates for systemic clearance (CL), but age was the only significant covariate for volume of distribution at steady state (Vss). There were significant age- and genotype-related differences and a significant age x genotype interaction in CL (20.6+/-11.0/12.7+/-4.0/3.2+/-1.0 and 5.4+/-4.0/3.7+/-1.4/2.1+/-0.7 L/h for homozygous extensive metabolisers [EMs]/heterozygous EMs/poor metabolisers [PMs] of the young and the elderly groups, respectively). In Vss, a significant difference was found between the young and the elderly groups (219+/-115 and 107+/-44.5 mL/kg, respectively), but not between three genotypes (178+/-142, 173+/-79 and 110+/-51 mL/kg for homozygous EMs, heterozygous EMs and PMs, respectively). CONCLUSION: The elderly EMs showed wide variance in the in vivo CYP2C19 activity and were phenotypically closer to the elderly PMs than the young EMs were to the young PMs. Some of the elderly homozygous EMs, as well as heterozygous EMs, have a metabolic activity similar to PMs, and the CYP2C19 genotype may therefore not be as useful as phenotyping in the elderly.     

Non‐antiplatelet effect of clopidogrel: improving endothelial function in Chinese healthy subjects with different CYP2C19 genotype

Clopidogrel has been shown to improve endothelial function in vitro and in patients with coronary artery disease. However, it remains unclear whether such an effect of clopidogrel is associated with CYP2C19 polymorphisms that determine the antiplatelet effect of clopidogrel. After genotyping, 12 healthy participants were enrolled in the study. Among them, six participants were CYP2C19*1/*1 (extensive metabolizers; EM) and the other six participants were CYP2C19*2/*2 or *3 (poor metabolizers; PM). All participants received 300 mg clopidogel orally. Endothelial function was assessed by measurement of flow‐mediated dilation of the brachial artery, and adenosine diphosphate‐induced platelet aggregation was determined by using optical aggregometry at 0, 4 and 24 h after administration of 300 mg clopidogrel. Flow‐mediated dilation was significantly higher at 4 and 24 h after a loading‐dose administration of clopidogrel in both the CYP2C19 EM and PM groups, but showed no significant difference between the two groups. Adenosine diphosphate‐induced platelet aggregation was significantly inhibited at 4 and 24 h after administration of clopidogrel in the CYP2C19 EM group. However, there was no statistical correlation between the change in flow‐mediated dilation and adenosine diphosphate‐induced platelet aggregation in the two CYP2C19 groups. This is the first study to report that clopidogrel improves endothelial function in healthy Chinese subjects, which is unrelated with the CYP2C19 genotype and independent of antiplatelet action.     

多重耐药基因及细胞色素 P450酶2C19基因多态性与氯吡格雷抗凝疗效的关系

目的：研究多重耐药基因（MDR1）及细胞色素P450酶2C19（CYP2C19）基因多态性对急性冠脉综合征（ ACS）患者经皮冠状动脉介入（ PCI）术后氯吡格雷疗效的影响。方法根据所测定的血栓弹力图MAADP结果,将进行PCI治疗的冠心病患者分为3组：A（MAADP ＞47）组、B（31≤MAADP≤47）组、C（MAADP ＜31）组;分别用基因芯片法和测序法,检测CYP2C19、MDR1基因多态性,比较不同组间基因多态性分布情况。结果各组患者在MDR1基因多态性未见明显差异（P＞0.05）,CYP2C19慢代谢基因型患者比例在 A 组明显高于另2组（P＜0.05）。结论 CYP2C19基因多态性可以影响氯吡格雷的抗凝效果。     

Ligand-based design of a potent and selective inhibitor of cytochrome P450 2C19

A series of omeprazole-based analogues was synthesized and assessed for inhibitory activity against CYP2C19. The data was used to build a CYP2C19 inhibition pharmacophore model for the series. The model was employed to design additional analogues with inhibitory potency against CYP2C19. Upon identifying inhibitors of CYP2C19, ligand-based design shifted to attenuating the rapid clearance observed for many of the inhibitors. While most analogues underwent metabolism on their aliphatic side chain, metabolite identification indicated that for analogues such as compound 30 which contain a heterocycle adjacent to the sulfur moiety, metabolism primarily occurred on the benzimidazole moiety. Compound 30 exhibited improved metabolic stability (Cl(int) = 12.4 mL/min/nmol) and was selective in regard to inhibition of CYP2C19-catalyzed (S)-mephenytoin hydroxylation in human liver microsomes. Finally, representative compounds were docked into a homology model of CYP2C19 in an effort to understand the enzyme-ligand interactions that may lead to favorable inhibition or metabolism properties.     

Genetic polymorphism of cytochrome P450 2C19 in healthy Malaysian subjects

AIMS: Impaired S-mephenytoin 4'-hydroxylation is a well-described genetic polymorphism affecting drug metabolism in humans. Although ethnic differences in its distribution of polymorphism has been described, it is not known whether there is an ethnic heterogeneity of the structure and expression of the CYP2C19 enzyme in the Malaysian population. METHODS: Study subjects were 142 healthy, unrelated Malaysians aged 18-29 years. Baseline omeprazole and 2-h postingestion omeprazole and 5'-hydroxyomeprazole concentrations were measured for CYP2C19 phenotype determination. Identification of CYP2C19 genotypes was performed with the use of polymerase chain reaction. RESULTS: Phenotyping of CYP2C19 revealed that the prevalence of poor metabolizers (PMs) in the Malaysian population was 14.1%, whereas prevalence of PMs in genotyping was 12.6%. The PM genotypic prevalence rate was 5.6% in Malays, 19.1% in Chinese and 10.0% in Indian subjects. There were significant differences in PM genotypic prevalence rates among the three primary ethnic groups (P < or = 0.05). CONCLUSIONS: Phenotyping and genotyping revealed significant differences in the prevalence rates among the three ethnic groups in Malaysia, with Chinese recording highest prevalence.     

细胞色素P450 2C19单碱基突变位点CYP2C19m1的分析

目的:CYP2C19ml是引起CYP2C19酶活性缺陷的主要等位基因,有83％左右的慢代谢者含有CYP2C19ml等位基因,本文试图建立一步PCR测定CYP2C19ml等位基因的方法。方法:根据等位基因特异扩增(ASA)原理设计两对分别特异扩增野生型等位基因和突变型等位基因的引物,建立了一步PCR测定CYP2C19ml等位基因的方法。结果:对39位随机受试者进行了基因分型研究,发现3位CYP2C19ml纯合子、18位CYP2C19ml杂合子,其余18位为野生型纯合子。结论:说明效法能够用于测定CYP2C19ml等住基因,并且证明该法具有简便、快速和污染少的优点。