Influence of CYP2C9 and CYP2C19 genetic polymorphisms on pharmacokinetics and pharmacodynamics of gliclazide in healthy Chinese Han volunteers

Background and objective: CYP2C9 is the major contributor to gliclazide metabolic clearance in vitro, while the pharmacokinetics of gliclazide modified release are affected mainly by CYP2C19 genetic polymorphisms in vivo. This study aims to investigate the influence of CYP2C9 and CYP2C19 genetic polymorphisms on the pharmacokinetics and pharmacodynamics of gliclazide in healthy Chinese Han volunteers. Methods: Eighteen healthy Han subjects with various combinations of CYP2C9 and CYP2C19 genotypes received 80 mg gliclazide. Plasma gliclazide concentrations were measured by a liquid chromatography–tandem mass spectrometry method for 84 h and plasma glucose and insulin levels were measured up to 15 h post‐dose. Results and discussion: There was no difference in either pharmacokinetic and or pharmacodynamic parameters of gliclazide when group A (CYP2C9*1/*1, CYP2C19 extensive metabolizers) was compared with group B (CYP2C9*1/*3, CYP2C19 *1/*1). When group C (CYP2C9*1/*1 and CYP2C19 poor metabolizers) was compared with group A, the AUC_0–∞ and C_max in group C were significantly higher [83·94 ± 40·41 vs. 16·39 ± 5·10 μg·h/mL (P = 0·000) and 1·50 ± 0·85 vs. 0·45 ± 0·18 μg/mL (P = 0·000)], and the oral clearance was significantly lower [1·17 ± 0·63 vs. 5·38 ± 1·86 L/h (P = 0·000)]. The half‐life of gliclazide was also significantly prolonged in group C subjects when compared with that of group A (33·47 ± 12·39 vs. 19·34 ± 10·45 h), but the difference was not significant (P = 0·052). The increase in serum glucose level at 11 h after dosing (ΔC_glu11) in group C was significantly higher than that of group A (?1·08 ± 0·42 vs. 0·22 ± 1·01 mmol/L, P = 0·022). The corresponding insulin levels showed no difference between the two groups. Conclusion: CYP2C9*3 was not associated with any change in the disposition of gliclazide. CYP2C19 polymorphisms appear to exert the dominant influence on the pharmacokinetics of gliclazide in healthy Chinese Han subjects, and may also affect the observed pharmacodynamics of the drug as a result.     

CYP2C9, but not CYP2C19, polymorphisms affect the pharmacokinetics and pharmacodynamics of glyburide in Chinese subjects

BACKGROUND: Although cytochrome P450 (CYP) 2C9 was thought to be the main pathway for glyburide (INN, glibenclamide) metabolism in vivo, studies in vitro indicated that CYP2C19 had a more dominant effect. This study investigated the relative influence of CYP2C9 and CYP2C19 genotypes on the pharmacokinetics and pharmacodynamics of glyburide in Chinese subjects. METHODS: Three groups of healthy male Chinese subjects (n=6 per group) were enrolled, as follows: group I, CYP2C9*1/*1 and CYP2C19 extensive metabolizers (EMs); group II, CYP2C9*1/*1 and CYP2C19 poor metabolizers (PMs); and group III, CYP2C9*1/*3 and CYP2C19 EMs. Subjects received single oral doses of 5 mg glyburide. Multiple blood samples were collected, and the plasma glyburide concentrations were determined by an HPLC method. The plasma glucose and insulin concentrations were also measured up to 2 hours after dosing. RESULTS: No significant differences in glyburide pharmacokinetics were observed between CYP2C19 EM and PM subjects who had the CYP2C9*1/*1 genotype (group I versus group II). Their respective values for area under the plasma concentration-time curve from time 0 to infinity (AUC0-infinity) and elimination half-life (t1/2) were 0.46+/-0.13 microg.h/mL versus 0.57+/- 0.11 microg.h/mL (P=.569) and 2.09+/-0.22 hours versus 2.24+/- 0.27 hours (P=.721). However, significant increases in AUC(0-infinity) (125% and 82%; P=.008 and .024, respectively) and t1/2 (71% and 60%; P=.003 and .007, respectively) were observed when CYP2C9*1/*3 subjects (group III) were compared with CYP2C9*1/*1 subjects in group I or II. Blood glucose reductions at 2 hours after dosing were 41.8%, 23.9%, and 27.7% in groups I, II, and III, respectively (P=.029), and hypoglycemia developed in 3 of 6 CYP2C9*1/*3 carriers and 2 of 12 CYP2C9*1/*1 carriers. CONCLUSION: CYP2C9, but not CYP2C19, polymorphism appears to exert a dominant influence on glyburide pharmacokinetics and pharmacodynamics in vivo. Further studies in diabetic patients with long-term dosing are warranted to confirm these findings.     

Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel

BACKGROUND: Thienopyridines are metabolized to active metabolites that irreversibly inhibit the platelet P2Y(12) adenosine diphosphate receptor. The pharmacodynamic response to clopidogrel is more variable than the response to prasugrel, but the reasons for variation in response to clopidogrel are not well characterized. OBJECTIVE: To determine the relationship between genetic variation in cytochrome P450 (CYP) isoenzymes and the pharmacokinetic/pharmacodynamic response to prasugrel and clopidogrel. METHODS: Genotyping was performed for CYP1A2, CYP2B6, CYP2C19, CYP2C9, CYP3A4 and CYP3A5 on samples from healthy subjects participating in studies evaluating pharmacokinetic and pharmacodynamic responses to prasugrel (60 mg, n = 71) or clopidogrel (300 mg, n = 74). RESULTS: In subjects receiving clopidogrel, the presence of the CYP2C19*2 loss of function variant was significantly associated with lower exposure to clopidogrel active metabolite, as measured by the area under the concentration curve (AUC(0-24); P = 0.004) and maximal plasma concentration (C(max); P = 0.020), lower inhibition of platelet aggregation at 4 h (P = 0.003) and poor-responder status (P = 0.030). Similarly, CYP2C9 loss of function variants were significantly associated with lower AUC(0-24) (P = 0.043), lower C(max) (P = 0.006), lower IPA (P = 0.046) and poor-responder status (P = 0.024). For prasugrel, there was no relationship observed between CYP2C19 or CYP2C9 loss of function genotypes and exposure to the active metabolite of prasugrel or pharmacodynamic response. CONCLUSIONS: The common loss of function polymorphisms of CYP2C19 and CYP2C9 are associated with decreased exposure to the active metabolite of clopidogrel but not prasugrel. Decreased exposure to its active metabolite is associated with a diminished pharmacodynamic response to clopidogrel.     

CYP2C9 and CYP2C19 genetic polymorphisms: frequencies in the south Indian population

The aim of the study was to establish the frequencies of CYP2C9*1, *2, *3 and CYP2C19*1, *2 and *3 in the south Indian population and to compare them with the inter-racial distribution of the CYP2C9 and CYP2C19 genetic polymorphisms. Genotyping analyses of CYP2C9 and CYP2C19 were conducted in unrelated, healthy volunteers from the three south Indian states of Andhra Pradesh, Karnataka and Kerala, by the polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP). The allele frequencies of the populations of these three states were then pooled with our previous genotyping data of Tamilians (also in south India), to arrive at the distribution of CYP2C9 and CYP2C19 alleles in the south Indian population. Frequencies of CYP2C9 and CYP2C19 alleles and genotypes among various populations were compared using the two-tailed Fisher's exact test. The frequencies of CYP2C9*1, *2 and *3 in the south Indian population were 0.88 (95% CI 0.85-0.91), 0.04 (95% CI 0.02-0.06) and 0.08 (95% CI 0.06-0.11), respectively. The frequencies of CYP2C9 genotypes *1/*1, *1/*2, *1/*3, *2/*2, *2/*3 and *3/*3 were 0.78 (95% CI 0.74-0.82), 0.05 (95% CI 0.03-0.07), 0.15 (95% CI 0.12-0.18), 0.01 (95% CI 0.0-0.02), 0.01 (95% CI 0.0-0.02) and 0.0, respectively. CYP2C19*1, *2 and *3 frequencies were 0.64 (95% CI 0.60-0.68), 0.35 (95% CI 0.31-0.39) and 0.01 (95% CI 0.0-0.03), respectively. As a result of a significant heterogeneity, the data on CYP2C19 genotype frequencies were not pooled. The frequency of CYP2C9*2 mutant alleles in south Indians was higher than in Chinese and Caucasians, while CYP2C9*3 was similar to Caucasians. CYP2C19*2 was higher than in other major populations reported so far. The relatively high CYP2C19 poor-metabolizer genotype frequency of 12.6% indicates that over 28 million south Indians are poor metabolizers of CYP2C19 substrates.     

Influence of CYP2C9 and CYP2C19 genetic polymorphisms on warfarin maintenance dose and metabolic clearance

OBJECTIVE: Our objective was to determine the influence of cytochrome P450 (CYP) 2C9 and CYP2C19 genetic polymorphisms on warfarin dose requirement and metabolic clearance. METHODS: The study population consisted of 93 Italian outpatients receiving long-term warfarin anticoagulant therapy (international normalized ratio values, 2-3), divided into 3 dose groups: low (<26.25 mg/wk; n = 37), medium (26.25-43.75 mg/wk; n = 32), and high (>43.75 mg/wk; n = 24). Steady-state unbound plasma concentrations of S- and R-warfarin were measured by HPLC and equilibrium dialysis, and corresponding unbound oral clearance (CL(free)) values were calculated. Allelic variants of CYP2C9 (CYP2C9(*)2 and CYP2C9(*)3) and CYP2C19 (CYP2C19(*)2) were identified by polymerase chain reaction, followed by restriction enzyme analysis. RESULTS: Fifty-four patients carried no CYP2C9 mutated alleles ((*)1/(*)1), 31 carried one ((*)1/(*)2, n = 15; and (*)1/(*)3, n = 16), and 8 carried two ((*)2/(*)2, n = 2; (*)3/(*)3, n = 2; and (*)2/(*)3, n = 4). Two subjects were homozygous and 19 were heterozygous for the CYP2C19(*)2 allele variant. The frequencies of CYP2C9 mutated alleles were 72% in the low-dose group, 36% in the medium-dose group, and 4% in the high-dose group; the corresponding mean S-warfarin CL(free) values were 307.5 mL/min, 480.3 mL/min, and 881.3 mL/min. The mean S-warfarin CL(free) values varied significantly among the CYP2C9 genotype groups (P <.0001), although most patients (72%) with no mutated alleles showed S-warfarin CL(free) values in the same range as those carrying mutated alleles (58-777 mL/min). No relationship was found between S-warfarin CL(free) and CYP2C19 genotype or between R-warfarin CL(free) and either CYP2C9 or CYP2C19 genotype. CONCLUSION: CYP2C9 genetic polymorphisms markedly influence warfarin dose requirements and metabolic clearance of the S-warfarin enantiomer, although nongenetic factors may also contribute to their large interindividual variability.     

Genetic polymorphisms of drug-metabolizing enzymes CYP2D6, CYP2C9, CYP2C19 and CYP3A5 in the Greek population

The aim of the present study was to determine the prevalence of the most common allelic variants of the polymorphic cytochrome P450 (CYP) enzymes CYP2D6, CYP2C9, CYP2C19 and CYP3A5 and to predict the genotype frequency for each polymorphism in the Greek population. DNA isolated from peripheral blood samples derived from 283 non-related Greek ethnic subjects was used to determine the frequency of CYP2D6*3, CYP2D6*4, CYP2C9*2, CYP2C9*3 and CYP3A5*3 allelic variants by the polymerase chain reaction (PCR)-restriction fragment length polymorphism method, CYP2C19*2 and CYP2C19*3 with allelic specific amplification (PCR-ASA), and CYP2D6*2 (gene duplications) by long PCR analysis. The allelic frequencies (out of a total of 566 alleles) for CYP2D6*3 and CYP2D6*4, were 2.3% and 17.8%, respectively, while gene duplications (CYP2D6*2) were found in 7.4% of the subjects tested. For CYP2C9*2 and CYP2C9*3 polymorphisms the allelic frequencies were 12.9% and 8.13% respectively. For CYP2C19, the *2 polymorphism was present at an allelic frequency of 13.1%, while no subjects were found carrying the CYP2C19*3 allele. Finally, the CYP3A5*3 allele was abundantly present in the Greek population with an allelic frequency of 94.4%. Overall our results show that the frequencies of the common defective allelic variants of CYP2C9, CYP2C19 and CYP3A5 in Greek subjects are similar to those reported for several other Caucasian populations. Finally, a high prevalence of CYP2D6 gene duplication among Greeks was found, a finding that strengthens the idea that a South/North gradient exists in the occurrence of CYP2D6 ultrarapid metabolizers in European populations.     

Clinical relevance of genetic polymorphisms in the human CYP2C9 gene

Cytochrome p450 (CYP) 2C9 hydroxylates about 16% of drugs in current clinical use. Of special interest are those with a narrow therapeutic index, such as S-warfarin, tolbutamide and phenytoin, where impairment in CYP2C9 metabolic activity might cause difficulties in dose adjustment as well as toxicity. Single-nucleotide polymorphisms (SNP) in the CYP2C9 gene have increasingly been recognized as determinants of the metabolic phenotype that underlies interindividual and ethnic differences. Apart from the wild-type protein CYP2C9*1 at least five allelic variants produce allozymes with reduced or deficient metabolic activity. Among white populations only CYP2C9*2 and CYP2C9*3 variants are of significance, with allelic frequencies of 0.08-0.14 and 0.04-0.16, respectively. In contrast, in Africans (African-Americans and Ethiopians) and Asians both variants are much less frequent (0.005-0.04), and CYP2C9*2 has not yet been detected in Asians. CYP2C9*4 has been exclusively identified in Japanese patients, and CYP2C9*5 and *6 were only found among African-Americans with a low allelic frequency of 0.017 and 0.006, respectively. Furthermore in Japanese a CYP2C9 promotor variant of four linked SNPs was correlated with reduced intrinsic clearance of phenytoin in vitro. Subjects who are carriers of one or more variant alleles may be at risk for adverse drug reactions/toxicities when prescribed drugs extensively metabolized by CYP2C9.     

Induction of CYP2C19 and CYP3A activity following repeated administration of efavirenz in healthy volunteers

Drug-drug interactions involving efavirenz are of major concern in clinical practice. We evaluated the effects of multiple doses of efavirenz on omeprazole 5-hydroxylation (CYP2C19) and sulfoxidation (CYP3A). Healthy volunteers (n = 57) were administered a single 20 mg oral dose of racemic omeprazole either with a single 600 mg oral dose of efavirenz or after 17 days of administration of 600 mg/day of efavirenz. The concentrations of racemic omeprazole, 5-hydroxyomeoprazole (and their enantiomers), and omeprazole sulfone in plasma were measured using a chiral liquid chromatography-tandem mass spectrometry method. Relative to single-dose treatment, multiple doses of efavirenz significantly decreased (P < 0.0001) the area under the plasma concentration-time curve from 0 to infinity (AUC(0-∞)) of racemic-, R- and S-omeprazole (2.01- to 2.15-fold) and the corresponding AUC(0-∞) metabolic ratio (MR) for 5-hydroxyomeprazole (1.36- to 1.44-fold) as well as the MR for omeprazole sulfone (～2.0) (P < 0.0001). The significant reduction in the AUC of 5-hydroxyomeprazole after repeated efavirenz dosing suggests induction of sequential metabolism and mixed inductive/inhibitory effects of efavirenz on CYP2C19. In conclusion, efavirenz enhances omeprazole metabolism in a nonstereoselective manner through induction of CYP3A and CYP2C19 activity.     

CYP2C9 allele variants in Chinese hypertension patients and healthy controls

BACKGROUND: Cytochromes P450 (CYP) 2C9 are polymorphic enzymes which catalyze a wide spectrum of drugs. It is also responsible for the metabolism of arachidonic acid into EETs. EETs are known to be a vasoactive substance and play an important role in a hypertensive episode. Whether the genetic polymorphism of CYP2C9 will affect the vasoactive effect and consequently affect hypertension formation is still unknown. We investigated the association of CYP2C9*2, CYP2C9*3 and CYP2C9*6 with hypertension. METHODS: Two hundred and thirty-nine hypertension patients and 265 healthy controls participated in our study. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to identify CYP2C9*2, CYP2C9*3 and CYP2C9*6. RESULTS: CYP2C9*2 and CYP2C9*6 were not detected in our study. The allelic frequency of CYP2C9*3 was 0.015 in hypertension patients in our study. In healthy controls, the allelic frequency of CYP2C9*3 was 0.049. Significant difference existed in CYP2C9*3 frequency between hypertension patients and healthy controls (0.015 for hypertension patients vs. 0.049 for healthy controls; chi2 = 9.728, P < 0.005, OR = 0.277, 95% CI: 0.118-0.651). Also, gender-dependent difference was observed. In females, CYP2C9*3 frequency of hypertension patients was significantly lower than that of healthy controls (chi2 = 11.513, P < 0.001, OR = 0.113, 95% CI: 0.026-0.500). CONCLUSION: To our knowledge, this is the first report on CYP2C9 frequencies in hypertension patients. Our study implied that CYP2C9*3 had a secondary protective effect in females, which may be useful for studying hypertension pathogenesis and therapeutics.     

Influence of CYP2C9 polymorphisms on the pharmacokinetics and cholesterol-lowering activity of (-)-3S,5R-fluvastatin and (+)-3R,5S-fluvastatin in healthy volunteers

INTRODUCTION: In vitro data indicate that biotransformation of the synthetic 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor fluvastatin is catalyzed by the cytochrome P450 (CYP) enzyme 2C9. The consequences of CYP2C9 genetic polymorphisms on fluvastatin pharmacokinetics and on its efficacy have not been investigated in humans thus far. METHODS: Twenty-four healthy heterozygous or homozygous carriers of the CYP2C9 variants Arg144Cys (*2) and Ile359Leu (*3) and 2 individuals with the deficient CYP2D6 genotype *4/*4 took 40 mg racemic fluvastatin daily for 14 days. All subjects had also been genotyped for CYP2C8, CYP2C19, and CYP2D6 polymorphisms. Pharmacokinetics was analyzed after the first fluvastatin administration. Serum lipid concentrations were measured before fluvastatin intake and on day 15. Plasma concentrations of (+)-3R,5S-fluvastatin and of (-)-3S,5R-fluvastatin were quantified by enantiospecific HPLC. RESULTS: Pharmacokinetics of both enantiomers showed statistically significant differences according to the number of CYP2C9*3 alleles (P <.0001, F test). Mean (and SD) values for area under the curve of the active (+)-3R,5S-fluvastatin in carriers of the genotype CYP2C9*1/*1, *1/*3, and *3/*3 were 173 (85) micro g. L(-1). h, 231 (85) micro g. L(-1). h, and 533 (120) micro g. L(-1). h, respectively. The corresponding values for area under the curve of (-)-3S,5R-fluvastatin were 227 (133) micro g. L(-1). h, 360 (103) micro g. L(-1). h, and 1126 (311) micro g. L(-1). h for CYP2C9*1/*1, *1/*3, and *3/*3, respectively. The CYP2C9*2 variant did not have any significant influence on fluvastatin kinetics, nor did the CYP2C8*3 allele, which was tightly linked with CYP2C9*2. Total serum cholesterol and low-density lipoprotein cholesterol concentrations decreased significantly during the 14-day treatment period (P <.001), but no correlation with the CYP2C9 genotype was found. CONCLUSIONS: The pharmacokinetics of both enantiomers of fluvastatin depended on the CYP2C9 genotype, with a 3-fold group mean difference in the active enantiomer and even greater differences in the inactive enantiomer, but differences in plasma concentrations were not reflected in cholesterol lowering after 14 days of fluvastatin intake in healthy volunteers.     

Dose-dependent effects of glyburide on insulin secretion and glucose uptake in humans

OBJECTIVE: To examine the relationship between plasma glyburide concentrations (0, 50, 100, 200, 400, and 800 nM) and the insulin response and glucose metabolism during euglycemic (4.6 +/- 0.1 mM) and hyperglycemic (11.6 +/- 0.2 mM) conditions. RESEARCH DESIGN AND METHODS: Nine healthy subjects participated in the study. Steady-state plasma glyburide concentrations were achieved by primed continuous intravenous infusion of glyburide. RESULTS: During both euglycemia and hyperglycemia, glyburide enhanced insulin secretion and glucose disposal only to drug levels of 100-200 nM corresponding to an oral dose less than or equal to 10 mg. CONCLUSIONS: The data suggest that glyburide (and probably other sulfonylureas), operates within a narrow range of plasma concentrations (50-200 nM), which can be achieved with very low doses of the drug. It remains to be shown whether the threshold of maximal effect also in clinical practice is achieved with lower sulfonylurea doses than that currently used.     

Interindividual variability in ibuprofen pharmacokinetics is related to interaction of cytochrome P450 2C8 and 2C9 amino acid polymorphisms

OBJECTIVE: Our objective was to identify genetic factors related to interindividual variability in the pharmacokinetics of ibuprofen and its enantiomers. METHODS: The time course for ibuprofen plasma concentration was measured by HPLC in 130 healthy individuals who received a single oral dose of 400 mg racemic ibuprofen. Genomic deoxyribonucleic acid was analyzed for common mutations at CYP2C8 and CYP2C9 genes that cause amino acid substitutions. RESULTS: Ibuprofen clearance values were 4.04 L/h (95% confidence interval [CI], 3.61-4.47 L/h), 2.79 L/h (95% CI, 2.07-3.52 L/h), and 0.40 L/h (95% CI, 0.37-0.43 L/h) for carriers of CYP2C8 genotypes *1/*1, *1/*3, and *3/*3, respectively, and 4.43 L/h (95% CI, 3.94-4.92 L/h), 3.26 L/h (95% CI, 2.53-3.99 L/h), 2.91 L/h (95% CI, 1.52-4.30 L/h), 2.05 L/h (95% CI, 0-6.37 L/h), 1.83 L/h (95% CI, 1.24-2.41 L/h), and 1.13 L/h (95% CI, 0.58-1.66 L/h) for carriers of the CYP2C9 genotypes *1/*1, *1/*2, *1/*3, *2/*2, *2/*3, and *3/*3, respectively. The P values for comparison across nonmutated, heterozygous, and homozygous genotypes were as follows: P <.001 for CYP2C8*3, P <.005 for CYP2C9*2, and P <.001 for CYP2C9*3. The main genetic factor for reduced clearance of R-(-)-ibuprofen is the CYP2C8*3 allele, whereas the clearance for S-(+)-ibuprofen is influenced by CYP2C8*3 and CYP2C9*3 alleles to a similar extent. The CYP2C9*2 allele was associated with low clearance only when it was present in combination with the CYP2C8*3 allele. As compared with individuals with no mutations, individuals with the common genotype CYP2C8*1/*3 plus CYP2C9*1/*2 (19% of the population) displayed decreased ibuprofen clearance (mean, 65% [95% CI, 42%-89%]; P <.001). Individuals homozygous or double-heterozygous for CYP2C8*3 and CYP2C9*3 variant alleles (8% of the population) had extremely low ibuprofen clearance rates, with values ranging from 7% to 27% of the mean clearance rates among noncarriers of mutations (P <.001). No enantiospecific reduction of ibuprofen clearance was observed. CONCLUSION: Low ibuprofen clearance occurs in a substantial proportion of healthy subjects, is not enantiospecific, and is strongly linked to CYP2C8 and CYP2C9 polymorphisms.     

Evaluation of the relationship between polymorphisms in CYP2C19 and the single‐dose pharmacokinetics of omeprazole in healthy Chinese volunteers: A multicenter study

The aim of this study was to evaluate the relationship between polymorphisms in CYP2C19 and the single‐dose pharmacokinetics (PKs) of omeprazole in healthy Chinese volunteers. A 20 mg single dose of omeprazole (Losec) enteric‐coated capsules or tablets was orally administered to 656 healthy subjects from eight subcenters. The polymorphic alleles of CYP2C19*2, *3, and *17 were determined by Sanger sequencing and Agena mass array. Plasma concentrations of omeprazole were determined by high‐performance liquid‐chromatography tandem mass spectrometry. PK parameters of area under the concentration versus time curve (AUC)_0‐t, AUC from zero to infinity (AUC_0‐∞), maximum plasma concentration (C_max), and terminal half‐life (t_1/2) were significantly influenced by CYP2C19 phenotype (all p < 0.001) and diplotype (all p < 0.001), and the same results were obtained in the subgroup analysis of the effects of diet and dosage form. The polymorphisms of CYP2C19*2(rs4244285; all PK parameters p < 0.001) and *3(rs4986893; p _Cmax = 0.020, and the p values of other PK parameters were less than 0.001) were significantly associated with the PKs of omeprazole. For CYP2C19*17 (rs12248560), only t_1/2 showed a significant correlation (p = 0.032), whereas other PK parameters did not. The present study demonstrated that the Pks of omeprazole is greatly influenced by CYP2C19.     

CYP2C9和VKORC1基因多态性检测试剂盒的性能验证

目的 对华法林代谢相关的人细胞色素P450超家族第二亚家族C9代谢酶(CYP2C9)和维生素K环氧化物还原酶复合体亚单位1(VKORC1)基因多态性检测试剂盒进行性能验证.方法 根据中国合格评定国家认可委员会(CNAS)制定的有关要求,结合试剂说明书,从符合率、精密度、检出限、抗干扰能力4个方面对苏州旷远生物分子技术有...     

CYP2D6 gene test in psychiatric patients and healthy volunteers

BACKGROUND: Antipsychotic drug therapy meets difficulties in predicting response in psychiatric patients. The medical treatment of these patients may be improved significantly by systematic phamacogenetic diagnosis identifying the drug metabolic capacities of each patient. Genetic polymorphisms in the coding sequence for the drug metabolizing cytochrome P450 enzyme CYP2D6 represent a pharmacogenetic target. METHODS: A cohort (n = 225) representing psychiatric patients seen during an 18-month trial period was included in the project after the subjects accepted a blood sample being taken to analyse their CYP2D6 allelic composition. To investigate any putative difference in allele frequencies among the psychiatric patients compared to earlier publications on allele frequencies in Caucasian populations, another cohort (n = 122) of local healthy volunteers was likewise included. RESULTS: Allelic frequencies in the psychiatric patients and healthy volunteers were indistinguishable. Alleles *1 and *2 encoding for normal enzyme activity and alleles *3, *4, *5, *6, *13/*16 representing non-active forms were found as well as alleles *9, *10, *41 encoding for enzymes with decreased activity. Furthermore, examples of the previously described duplications of *1 and *2, which result in enhanced enzyme activity, were also identified. CONCLUSION: A systematic CYP2D6 gene test of hospitalized psychiatric patients revealed the identification of pharmacogenetically relevant alleles affecting capacity to metabolize antipsychotics. The frequencies of phenotypes in affected patients were 8.4 % intermediate metabolizers (IMs), 8.4 % poor metabolizers (PMs) and 3.1 % ultrafast metabolizers (UMs), whereas 52.4 % were extensive metabolizers (EMs) and 27.6 % heterozygous EMs.