Pharmacokinetics of losartan and its metabolite E-3174 in relation to the CYP2C9 genotype

BACKGROUND AND AIM: Losartan is metabolized by polymorphic CYP2C9 to E-3174. Our aim was to evaluate the pharmacokinetics of losartan and E-3174 in relation to the CYP2C9 genotype. METHODS: A 50-mg oral dose of losartan was given to 22 Swedish volunteers with different CYP2C9 genotypes. Losartan and E-3174 were analyzed by HPLC in plasma and urine samples collected up to 24 hours after drug intake. Furthermore, losartan and E-3174 were analyzed in 8-hour urine samples collected from 17 Spanish subjects after a single oral dose of 25 mg losartan. RESULTS: The maximum plasma concentration of E-3174 was significantly (P <.05) lower in the CYP2C9*1/*3 (n = 5) and CYP2C9*2/*3 (n = 4) groups compared with the CYP2C9*1/*1 (n = 6) and CYP2C9*1/*2 (n = 3) groups and extremely low in 1 subject with the CYP2C9*3/*3 genotype. The ratio of the total losartan area under the plasma concentration-time curve (AUC) to the total E-3174 AUC (AUC(losartan)/AUC(E-3174)) was higher in the subject with the CYP2C9*3/*3 genotype (30-fold) and also in the CYP2C9*1/*3 and *2/*3 groups (approximately 2- and 3-fold, respectively) compared with the CYP2C9*1/*1 group. The plasma ratios correlated significantly with the 0- to 8-hour urinary losartan/E-3174 ratios. Among the total of 39 subjects, the urinary ratio was significantly higher in subjects with the CYP2C9*1/*3 (n = 10) and *2/*3 (n = 4) genotypes than in those with the CYP2C9*1/*1 genotype (n = 11; P <.01) and approximately 40-fold higher in subjects with the CYP2C9*3/*3 genotype (n = 3). CONCLUSION: The CYP2C9*3 allele was shown to be associated with decreased formation of E-3174 from losartan. The significant differences between genotypes in plasma and urine losartan/E-3174 ratios and the good correlation between the plasma and urine ratios suggest that the losartan/E-3174 ratio in 0- to 8-hour urine specimens may serve as a phenotyping assay for CYP2C9 activity. Further studies in larger populations will be required to establish this.     

Functional impact of CYP2C95, CYP2C96, CYP2C98, and CYP2C911 in vivo among black Africans

Background and aim Previous data indicate that the urinary losartan/E-3174 ratio is a marker for cytochrome P450 (CYP) 2C9 activity in vivo. The functional impact of CYP2C9*5, *6, *8, and *11 polymorphisms in vivo has not been investigated previously in humans. METHODS: A single oral dose of losartan (25 mg) was given to 19 Beninese subjects with CYP2C9*1/*1 (n = 9), *1/*5 (n = 1), *1/*6 (n = 1), *1/*8 (n = 2), *1/*11 (n = 3), *5/*6 (n = 1), *5/*8 (n = 1), and *8/*11 (n = 1) genotypes. Concentrations of losartan and its active metabolite E-3174 were determined in urine from 0 to 8 hours by HPLC. The losartan/E-3174 metabolic ratio was used as a measure of losartan oxidation in vivo. RESULTS: The urinary losartan/E-3174 ratio in the various genotypes was as follows: 1.85 +/- 2.4 (mean +/- SD) for CYP2C9*1/*1, 14.6 for CYP2C9*1/*5, 4.2 for CYP2C9*1/*6, 188 for CYP2C9*5/*6, 11.6 for CYP2C9*5/*8, 0.44 +/- 0.13 (mean +/- SD) for CYP2C9*1/*8, 2.2 for CYP2C9*8/*11, and 5.72 +/- 4.5 (mean +/- SD) for CYP2C9*1/*11. Compared with the CYP2C9*1/*1 genotypes, the losartan/E-3174 ratio was significantly different in the CYP2C9*5 allele carriers (CYP2C9*1/*5, CYP2C9*5/*8, and CYP2C9*5/*6 genotypes) (P =.01, Mann-Whitney) but was not different in CYP2C9*1/*8 (P =.16) and CYP2C9*1/*11 (P =.11) carriers. The urinary losartan/E-3174 ratio of the single CYP2C9*1/*6 subject was higher than the 95% confidence interval of the mean of the CYP2C9*1/*1 group (0.0-3.7), whereas the metabolic ratio of the CYP2C9*8/*11 carrier was inside the 95% confidence interval of the means of the CYP2C9*1/*1 and CYP2C9*1/*11 groups (0.0-18). CONCLUSIONS: The CYP2C9*5 and *6 alleles are associated with decreased enzyme activity in vivo compared with the wild-type variant, whereas the CYP2C9*8 and *11 variants did not appear to have large in vivo effects.     

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.     

CYP3A5*3 influences sirolimus oral clearance in de novo and stable renal transplant recipients

BACKGROUND: The low and highly variable oral bioavailability of the immunosuppressant sirolimus is thought to result partly from genetic polymorphism of the CYP3A5 gene. METHODS: This study aimed to evaluate the contribution of the CYP3A5 single-nucleotide polymorphism A6986G to the interindividual variability of sirolimus pharmacokinetics in 47 renal transplant patients at steady state, 21 of whom were also followed up for the first 3 months after transplantation. The patients were administered sirolimus, mycophenolate mofetil, and corticosteroids but no calcineurin inhibitor. They were genotyped for CYP3A5*3 by use of real-time quantitative polymerase chain reaction based on the 5'-nuclease allelic discrimination assay. Full sirolimus blood concentration profiles were measured at steady state (3 months after transplantation or more) in all patients, as well as at weeks 1 and 2 and month 1 in 21 of these patients, by use of liquid chromatography-tandem mass spectrometry. The sirolimus area under the concentration-time curve (AUC) was calculated via the standard noncompartmental approach. Maximal concentration (C(max)) and trough level (C(0)) values were measured. RESULTS: Significantly lower AUC/dose, C(max)/dose, and C(0)/dose values were found at steady state (n = 47) in individuals carrying at least 1 CYP3A5*1 allele (n = 6) than in *3/*3 patients (26.6 +/- 15.7 versus 51.1 +/- 21.1 [P = .008], 4.8 +/- 3.3 versus 7.7 +/- 3.3 [P = .02], and 1.5 +/- 0.8 versus 3.0 +/- 1.5 [P = .01], respectively), as well as during all posttransplant periods in the subgroup of 21 patients who were followed up for the first 3 months after transplantation (n = 21) (P < .05 always). Patients with the CYP3A5*1/*1 and *1/*3 genotypes required a significantly higher sirolimus daily dose to achieve the same blood concentration at steady state as *3/*3 patients. In patients followed up for the first 3 months after transplantation, C(0) levels within the target range were only achieved after 1 to 3 months of repeated dosing and dose adjustment in both genotypic groups. CONCLUSION: These results confirm that sirolimus metabolic activity and oral clearance are significantly decreased in patients who are homozygous for the CYP3A5*3 single-nucleotide polymorphism and suggest that the determination of this polymorphism could be useful for a priori dose adjustment of sirolimus, given the long half-life of this drug.     

Polymorphism in CYP2C8 is associated with reduced plasma concentrations of repaglinide

OBJECTIVE: Our objective was to investigate the effects of genetic polymorphisms of cytochrome P450 (CYP) 2C8 on the pharmacokinetics and pharmacodynamics of the meglitinide analog antidiabetic drug repaglinide. METHODS: We genotyped 28 healthy volunteers who had participated in our pharmacokinetic studies on repaglinide for variant alleles of the CYP2C8 gene. Each subject ingested a 0.25-mg dose of repaglinide, and plasma drug and blood glucose concentrations were monitored for 7 hours after dosing. RESULTS: There were 19 subjects (68%) with the CYP2C8*1/*1 genotype (wild type), 6 subjects (21%) with the CYP2C8*1/*3 genotype, and 3 subjects (11%) with the CYP2C8*1/*4 genotype. In the 3 genotypic groups, the mean +/- SD area under the plasma repaglinide concentration-time curve from time 0 to infinity [AUC(0- infinity )] was 5.8 +/- 2.5 ng. h/mL for CYP2C8*1/*1, 3.6 +/- 0.9 ng. h/mL for CYP2C8*1/*3, and 5.1 +/- 3.6 ng. h/mL for CYP2C8*1/*4. The mean AUC(0- infinity ) of repaglinide was 45% (P <.005) lower and the peak concentration in plasma was 39% lower (P <.05) in subjects with the CYP2C8*1/*3 genotype compared with those with the CYP2C8*1/*1 genotype. No statistically significant differences were found in the blood glucose response to repaglinide between the genotypes. CONCLUSIONS: Unexpectedly, the CYP2C8*3 variant allele was associated with reduced plasma concentrations of repaglinide. The effects of CYP2C8 polymorphisms on the pharmacokinetics of CYP2C8 substrates warrant further study.     

高分辨熔解方法的建立及在真菌感染患者CYP2C19遗传多态性检测中的应用

目的 探讨高分辨熔解方法 (high resolution melting,HRM)检测真菌感染患者CYP2C19遗传多态性的可行性.方法 建立HRM方法 检测CYP2C19 * 2和CYP2C19 * 3两个多态性位点的基因型,并与传统方法 PCR-限制性片段长度多态性(PCR-RFLP)及序列分析结果 相比较,进一步应用于47例真菌感染患者基因型的检测与分析.结果 2种方法 检测CYP2C19 * 2和CYP2C19* 3基因型结果 完全一致,与DNA序列分析结果 也相吻合,而HRM方法 操作更为简便,耗时更短.47份临床标本检测结果 显示,CYP2C19的2个多态性位点存在不同基因型,CYP2C19 * 1/ * 1所占比例为48.9%(23/47),CYP2C19 * 1/ * 2为25.5%(12/47),CYP2C19 * 1/ * 3为6.4%(3/47),CYP2C19 * 2/ * 2为12.8%(6/47),CYP2C19 * 2/ * 3为6.4%(3/47).结论 HRM方法 能有效检测CYP2C19基因多态性,且较PCR-RFLP方法 更为简便、快速.此外,CYP2C19基因在真菌感染患者中存在明显的遗传多态性.     

Effect of the CYP2C9*3 allele on lornoxicam metabolism

BACKGROUND: We investigated whether the CYP2C9 genotypes would affect lornoxicam metabolism in healthy volunteers. METHODS: Twelve healthy volunteers who had been genotyped for CYP2C9 gene were selected to participate in our study. After 8 mg lornoxicam was taken, blood samples were drawn from 0 to 36 h. The plasma concentrations of lornoxicam and 5'-hydroxylornoxicam were determined by HPLC method. 5'-hydroxylornoxicam was purified from rabbits'urine by semi-preparative HPLC. RESULTS: Lornoxicam and 5'-hydroxylornoxicam both exhibit CYP2C9 genotype-dependent pharmacokinetic profiles. The area under the plasma concentration-time curve (AUC) of lornoxicam increased by 60 +/- 9.78% (P <0.05) and the AUC of 5'-hydroxylornoxicam decreased by 65 +/- 11.75% (p <0.001) in heterozygous CYP2C9*1/*3 subjects (n=6) compared with CYP2C9*1/*1 group (n=6). t1/2 value of lornoxicam and 5'-hydroxylornoxicam prolonged by 39 +/- 8.35% and curtailed by 59 +/- 6.83% respectively in CYP2C9*1/*3 subjects. But no significant differences in Tmax of lornoxicam and 5'-hydroxylornoxicam were observed between these 2 genotypes. In addition, for the first time we exploit the purification method for 5'-hydroxylornoxicam from rabbits' urine. CONCLUSION: The CYP2C9*3 allele significantly affected the metabolism of lornoxicam. The pharmacokinetic parameters of both lornoxicam and 5'-hydroxylornoxicam were significantly different between these 2 genotypes.     

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.     

CYP2C9 polymorphisms and the interindividual variability in pharmacokinetics and pharmacodynamics of the loop diuretic drug torsemide

INTRODUCTION: According to in vitro data, torsemide (INN, torasemide) is a substrate of the genetically polymorphic enzyme cytochrome P450 (CYP) 2C9, but the impact of CYP2C9 polymorphisms on torsemide pharmacokinetics and pharmacodynamics has not been studied in humans. METHODS: A total of 36 healthy volunteers (12, 9, 1, 9, 3, and 2 carriers of CYP2C9 genotypes *1/*1 , *1/*2 , *2/*2 , *1/*3 , *2/*3 , and *3/*3 , respectively) received a single oral dose of 10 mg torsemide for pharmacokinetic and pharmacodynamic analysis. The effects of the CYP2C9 polymorphism on torsemide-induced urine volume and urinary elimination of sodium, potassium, chloride, and uric acid were measured during a salt-restricted diet. RESULTS: Median torsemide total oral clearance values were 3.4, 2.2, and 1.2 L/h in carriers of the CYP2C9 genotypes *1/*1 , *1/*3 , and *3/*3 , respectively, but there was no significant difference related to CYP2C9*2 . Values for metabolite formation clearance via metabolites M1 and M5 were 1.4, 1.7, 1.4, 1.0, 0.77, and 0.18 L/h in carriers of genotypes *1/*1 , *1/*2 , *2/*2 , *1/*3 , *2/*3 , and *3/*3 , respectively (P < .001). From 0 to 8 hours after torsemide administration, Na + , K + , and Cl - elimination was higher in carriers of CYP2C9*3 alleles than in carriers of the homozygous wild-type genotype, and 24-hour uric acid elimination values in urine were 451, 350, and 249 mg in carriers of 0, 1, and 2 CYP2C9*3 alleles, respectively (P = .003). CONCLUSION: Torsemide pharmacokinetics differed significantly between subgroups with different CYP2C9 genotypes, and diuretic effects were slightly more exaggerated in carriers of CYP2C9*3 alleles. To answer the question of whether these findings have clinical implications, further studies in patients undergoing long-term torsemide treatment are required.     

CYP2C19 genotype affects diazepam pharmacokinetics and emergence from general anesthesia

OBJECTIVES: Diazepam is widely used to relieve preoperative anxiety in patients. The objective of this study was to investigate the effects of polymorphism in CYP2C19 and the effects of CYP3A4 messenger ribonucleic acid (mRNA) content in blood on recovery from general anesthesia and on diazepam pharmacokinetics. METHODS: Sixty-three Japanese patients were classified into the following 3 genotype (phenotype) groups on the basis of polymerase chain reaction-restriction fragment length polymorphism analysis of CYP2C19 polymorphism: no variants, *1/*1 (extensive metabolizer [EM]); 1 variant, *1/*2 or *1/*3 (intermediate metabolizer [IM]); and 2 variants, *2/*2, *2/*3, or *3/*3 (poor metabolizer [PM]). We assessed the effects of these polymorphisms and of CYP3A4 mRNA content in the lymphocytes on the patients' recovery from general anesthesia. RESULTS: CYP2C19 genotyping analysis in the 63 subjects showed that 32%, 46%, and 22% of subjects were classified into the EM, IM, and PM groups, respectively. The PM subjects showed a larger area under the curve representing the concentration of diazepam over a 24-hour period (AUC(0-24)) (2088 +/- 378 ng/mL.h(-1), P = .0259), lower clearance of diazepam (0.049 +/- 0.009 L.h(-1).kg(-1), P = .0287), and longer emergence time (median, 18 minutes; 25th-75th percentile range, 13-21 minutes; P < .001) in comparison with subjects in the EM group (AUC(0-24), 1412 +/- 312 ng/mL; clearance, 0.074 +/- 0.018 L.h(-1).kg(-1); and emergence time, 10 minutes, 8-12 minutes [median and 25th-75th percentile range]). The IM group also showed a longer emergence time (median, 13 minutes; 25th-75th percentile range, 9-20 minutes; P < .001) and a larger variation in this parameter in comparison with the EM group. The distributions of the CYP2C19 genotype were significantly different between the 2 groups (rapid emergence <20 minutes, slow emergence >20 minutes) (P = .0148). The mean value of the CYP3A4 mRNA level in the slow-emergence group (mean +/- SD, 4.80 +/- 3.99 x10(-10)) was significantly lower than that of the rapid-emergence group (mean +/- SD, 12.50 +/- 11.90 x10(-10)) (P = .0315). However, there was no significant correlation between emergence time and CYP3A4 mRNA levels (r = 0.239, P = .0601). CONCLUSION: We found that the CYP2C19 genotype affects diazepam pharmacokinetics and emergence from general anesthesia and that the slow-emergence group possesses lower levels of CYP3A4 mRNA than are found in the rapid-emergence group.     

华南地区汉族人群心脑血管相关基因多态性分析

目的了解心脑血管相关基因细胞色素P450酶(CYP)2C19、CYP2C9、维生素K环氧化物还原酶复合体1(VKORC1)和乙醛脱氢酶2(ALDH2)基因的单核苷酸多态性频率在华南地区汉族人群分布的情况。方法采用芯片技术对252例心脑血管疾病患者的CYP2C19、ALDH2、CYP2C9以及VKORC1位点基因多态性进行检测,并统计男女间基因型频率的差异。结果 CYP2C19的野生型*1/*1占42.5%,突变型*1/*2占36.9%,*1/*3占7.9%,*2/*2占9.9%,*2/*3占1.6%,*3/*3占1.2%,在男女人群间各类基因型的发生率差异无统计学意义(P0.05);CYP2C9只检测到2种等位基因CYP2C9*1/*1和CYP2C9*1/*3,男性基因频率分别为98.6%和1.4%,女性基因频率分别为90.1%和9.9%,在男女人群间的分布差异有统计学意义(P0.05);VKORC1有3种基因型AA、AG和GG,频率分别为80.6%、18.7%和0.8%,在男女人群间的分布差异无统计学意义(P0.05);ALDH2有3种基因型GG、GL和LL型,频率分别为55.2%、37.3%和7.5%,在男女人群间的分布差异无统计学意义(P0.05)。结论 CYP2C9的多态性分布与性别有关,CYP2C19、VKORC1和ALDH2的多态性分布与性别无关。     

武汉地区冠心病患者氯吡格雷药物代谢相关基因CYP2C19的多态性分布分析

目的 探讨武汉地区冠心病介入患者氯吡格雷代谢相关基因CYP2C19多态性的分布。方法 选取2014年1月～12月武汉大学人民医院心内科进行介入治疗(PCI)的316例冠心病患者作为研究对象。通过基因芯片法检测氯吡格雷代谢相关的CYP2C19*1,*2,*3基因,并将患者按CYP2C19基因型别分为不同代谢类型:强代谢型(*1/*1),中间代谢型(*1/*2,*1/*3),弱代谢型(*2/*2,*3/*3,*2/*3)。结果 根据CYP2C19基因多态性位点功能代谢分型,携带CYP2C19*1的强代谢型(*1/*1)占43.4%,携带CYP2C19*2或*3的中间代谢型(*1/*2和*1/*3)及弱代谢型(*2/*2,*2/*3和*3/*3)分别占42.4%,14.2%。不同性别在CYP2C19基因分型上差异无统计学意义。结论 武汉地区冠心病介入患者中分布有较多的CYP2C19氯吡格雷代谢功能缺失基因。     

Pharmacokinetics and toxicity of docetaxel: role of CYP3A, MDR1, and GST polymorphisms

OBJECTIVE: Patients initiating docetaxel chemotherapy were genotyped for CYP3A4, CYP3A5, MDR1, GSTM1, GSTT1, GSTM3, and GSTP1 to identify variability factors of docetaxel pharmacokinetics and toxicity. METHODS: Genotyping was performed by direct sequencing (CYP3A4), real-time polymerase chain reaction (CYP3A5), and polymerase chain reaction-restriction fragment length polymorphism (MDR1 and GST). The clearance and area under the curve of docetaxel were calculated by use of a Bayesian approach. Absolute neutrophil count was recorded twice weekly. RESULTS: With regard to the pharmacokinetic analysis, 58 patients were included. CYP3A4*1B carriers (*1A/*1B, n=4), who are also CYP3A5*1/*3 carriers, had a significantly higher clearance and lower dose-normalized area under the curve of docetaxel than those with the wild genotype (*1A/*1A, n=53): 55.2+/-13.5 L/h versus 37.3+/-11.7 L/h (P=.01) and 31.4+/-6.2 (microg . h/L)/(mg/m(2)) versus 52.7+/-18.2 (microg . h/L)/(mg/m(2)) (P=.005), respectively. No influence of MDR1 was evidenced. With regard to the pharmacodynamic analysis, febrile neutropenia occurred more frequently in GSTP1*A/*B carriers (31.6% versus 3.7% in *A/*A carriers and 0% in *A/*C, *B/*B, and *B/*C carriers) (P=.037). Grade 3 neutropenia occurred more frequently in 3435TT MDR1 genotype carriers: TT, 100%; CT, 77.3%; and CC, 54.5% (P=.046). No influence of GSTM1, GSTT1, or GSTM3 polymorphisms was evidenced on docetaxel toxicity. CONCLUSIONS: Patients carrying the CYP3A*1B allele may have enhanced docetaxel clearance and may be underexposed, whereas those carrying GSTP1*A/*B and 3435TT genotypes may have excessive hematologic toxicity. Further studies are warranted to determine the usefulness of genotyping before docetaxel treatment.     

St John's wort induces both cytochrome P450 3A4-catalyzed sulfoxidation and 2C19-dependent hydroxylation of omeprazole

OBJECTIVE: St John's wort, an extract of the medicinal plant Hypericum perforatum, is widely used as an herbal antidepressant. Although the ability of St John's wort to induce cytochrome P450 (CYP) 3A4-mediated reaction has been well established, the effect on CYP2C19 is still not determined. Thus the objective of this study was to determine the impact of St John's wort on the pharmacokinetic profiles of omeprazole and its metabolites. METHODS: Twelve healthy adult men (6 CYP2C19*1/CYP2C19*1, 4 CYP2C19*2/CYP2C19*2 and 2 CYP2C19*2/CYP2C19*3) were enrolled in a 2-phase randomized crossover design. In each phase the volunteers received placebo or a 300-mg St John's wort tablet 3 times daily for 14 days. Then all subjects took a 20-mg omeprazole capsule orally. Blood samples were collected up to 12 hours after omeprazole administration. Omeprazole and its metabolites were quantified by use of HPLC with ultraviolet detection. RESULTS: Omeprazole and its metabolites all exhibit CYP2C19 genotype-dependent pharmacokinetic profiles. After a 14-day treatment with St John's wort, substantial decreases in plasma concentrations of omeprazole were observed. The peak plasma concentration (C(max)) significantly decreased by 37.5% +/- 13.3% (P =.001) in CYP2C19*2/CYP2C19*2 or *3 and by 49.6% +/- 20.7% (P =.017) in CYP2C19*1/CYP2C19*1; the area under the concentration-time curve extrapolated to infinity [AUC(0- infinity )] decreased by 37.9% +/- 21.3% (P =.014) and 43.9% +/- 23.7% (P =.011) in CYP2C19 mutant and wild genotypes, respectively. Moreover, the C(max) and AUC(0- infinity ) of omeprazole sulfone increased by 160.3% +/- 45.5% (P =.001) and by 136.6% +/- 84.6% (P =.014), 155.5% +/- 58.8% (P =.001), and 158.7% +/- 101.4% (P =.017) in mutant and wild genotypes, respectively. St John's wort increased the C(max) of 5-hydroxyomeprazole by 38.1% +/- 30.5% (P =.028) and the AUC(0- infinity ) by 37.2% +/- 26% (P =.005) in CYP2C19 wild-type subjects, whereas it did not produce any significant alterations to the corresponding pharmacokinetic parameters in subjects with variant genotypes. CONCLUSION: St John's wort induces both CYP3A4-catalyzed sulfoxidation and CYP2C19-dependent hydroxylation of omeprazole and enormously decreases the plasma concentrations of omeprazole. Clinically relevant interactions with other drugs may occur and must be taken into account when St John's wort is being taken.     

赤峰地区蒙古族冠心病患者CYP2C19基因多态性分布研究

目的分析赤峰地区蒙古族冠心病患者CYP2C19基因多态性分布状况。方法选取2018年3-12月于该院确诊为冠心病并行经皮冠状动脉介入术治疗的患者558例为研究对象,其中蒙古族患者299例为研究组,汉族患者259例为对照组。抽取两组患者的外周血2 mL,提取基因组DNA,采用实时荧光定量PCR方法检测CYP2C19基因多态性,比较两组间CYP2C19基因型、代谢型分布情况。结果研究组患者CYP2C19*1/*1、*1/*2、*2/*3型所占比例均高于对照组(P<0.05);两组CYP2C19*1/*3、*2/*2、*3/*3型所占比例比较,差异无统计学意义(P>0.05)。研究组中间代谢型和慢代谢型基因所占比例低于对照组(P<0.05),快代谢型基因所占比例高于对照组(P<0.05)。结论赤峰地区蒙古族冠心病患者CYP2C19基因存在不同基因型和代谢型,与汉族冠心病患者间存在差异。掌握CYP2C19基因的多态性分布情况对冠心病患者抗凝药物的选择具有重要意义。     

CYP2C19 genetic mutations in North Indians

OBJECTIVES: To identify defective alleles of CYP2C19 (CYP2C19*2 and *3) in North Indians. METHODS: One hundred extensive metabolizers and 21 poor metabolizers of omeprazole were genotyped with respect to CYP2C19*2 and *3 alleles with polymerase chain reaction-based diagnostic tests. RESULTS: Fifty-two extensive metabolizers and six poor metabolizers were homozygous with the CYP2C19*1/*1 genotype, and 48 extensive metabolizers and six poor metabolizers were heterozygous with the CYP2C19*1/*2 genotype. Nine poor metabolizers were homozygous with the CYP2C19*2/*2 genotype. No extensive or poor metabolizers demonstrated the presence of the CYP2C19*3 allele. CYP2C19*2 could explain 43% (9/21) of the poor metabolizers and 57% (24/42) of the defective alleles in poor metabolizers. Allele frequency of CYP2C19*1 and *2 was 0.7 (95% confidence interval of 0.65 to 0.75) and 0.3 (95% confidence interval of 0.25 to 0.35), respectively. Homozygous extensive metabolizers excreted 7.85 +/- 7.6 micromol 5-hydroxyomeprazole in 8 hours, which was 28% more as compared with heterozygous extensive metabolizers who excreted 5.6 +/- 3.6 micromol 5-hydroxyomeprazole in 8 hours (P < .05). CONCLUSIONS: CYP2C19*2 demonstrated allele frequency of 0.3, whereas CYP2C19*3 was absent in North Indians. Because CYP2C19*2 is not able to explain 57% of poor metabolizers, other mutations (CYP2C19*4 to *8) might be present in North Indians. CYP2C19 demonstrated differential evolution in North Indians because the frequency of CYP2C19*2 was similar to that in Oriental subjects, but that of CYP2C19*3 was similar to that in white subjects.     

Cytochrome P450 CYP2C19 genotypes in Nigerian sickle‐cell disease patients and normal controls

Background and objective: Subjects with different CYP2C19 genotypes may metabolize proguanil, a pro‐drug used for malaria prophylaxis differently and the frequency of the different alleles may be different in patients with sickle‐cell disease (SCD) and normal controls. The objective of this study was to evaluate CYP2C19 *1, *2 and *3 allele and genotype frequencies in Nigerian normal controls and SCD patients, and to further compare variant CYP2C19 frequencies in Nigerians with other African populations. Methods: Genotyping was carried out with PCR and restriction fragment length polymorphism analysis. Results and discussion: CYP2C19 *1 (84·3 vs. 84·9%) or *2 allele frequency (15·7 vs. 15·1%) was not significantly different between patients with SCD and normal subjects. No *3 allele was detected in the cohort. The SCD group exhibited a statistically significantly lower frequency of *1/*1 genotype (69·6%) compared with normal controls (74·4%). Frequency of *2/*2 was significantly lower in SCD (0·9%) compared with normal controls (4·7%). Frequencies of *1/*2 (29·6 vs. 20·9%) were no different in SCD and normal controls. Conclusion: Prevalence of CYP2C19 polymorphisms was defined for the first time in Nigerian normal and SCD populations. Nigerian SCD patients exhibited significantly lower CYP2C19 *1/*1 and *2/*2 frequencies than normal controls. No differences were detected in CYP2C19 allele or genotype frequencies in normal subjects between this study and previous reports in other African populations.     

CYP3A5和多重耐药基因1多态性对肾移植患者他克莫司药代动力学参数的影响

目的探讨细胞色素P450,家族3,亚家族A,多肽5(CYP3A5)基因和多重耐药基因1(MDR1)C3435T多态性对肾移植患者他克莫司药代动力学参数的影响,在基因水平为临床合理用药提供参考。方法采用聚合酶链反应(PCR)和限制酶切片长多态性(RFIP)方法对63例肾移植术后患者进行CYP3A5和MDR1基因分型。移植手术1个月后进行血药浓度测定和药代动力学参数计算。结果携带CYP3A5*1基因型肾移植患者的剂量校正曲线下面积(AUC_(0-t))明显低于CYP3A5*3*3型患者,在随后对上述2组不同CYP3A5基因分型的患者进行MDR1的C3435T基因多态性分型研究表明,MDR1 C3435T基因多态性对他可莫司的药代动力学参数无明显影响。结论 CYP3A5基因多态性与他可莫司药代动力学参数相关,携带CYP3A5*1基因型肾移植患者比CYP3A5*3*3型患者需要较高的剂量才能达到目的浓度;而在影响他可莫司药代动力学参数的因素中MDR1 C3435T基因多态性不是重要因素。药代动力学参数的测定有利于器官移植患者剂量选择及个体化用药治疗。     

Influence of CYP2C9 genotypes on the pharmacokinetics and pharmacodynamics of piroxicam

OBJECTIVE: Our objective was to evaluate the influence of cytochrome P450 (CYP) 2C9 polymorphisms on the pharmacokinetics and pharmacodynamics of the nonsteroidal anti-inflammatory drug piroxicam. METHODS: Thirty-five healthy subjects with CYP2C9 genotypes *1/*1 (n=17), *1/*2 (n=9), and *1/*3 (n=9) received a single oral dose of piroxicam (20 mg). Blood samples were collected at various time points up to 240 hours for measurements of the concentrations of piroxicam and thromboxane B2 (TXB2). RESULTS: Piroxicam's area under the plasma concentration-time curve from time 0 to infinity and oral clearance corrected for body weight were 154+/-37 microg.mL-1.h and 2.0+/-0.5 mL.h-1.kg-1, respectively, in CYP2C9*1/*1 individuals, as compared with 256+/-97 mL.h-1 (P=.002) and 1.3+/- 0.4 mL.h-1.kg-1 (P=.002), respectively, in CYP2C9*1/*2 individuals and 259+/- 95 mL.h-1 (P=.002) and 1.3+/- 0.4 mL.h-1.kg-1 (P=.002), respectively, in CYP2C9*1/*3 individuals. There were no significant differences between CYP2C9*1/*2 and CYP2C 9*1/*3 individuals in these pharmacokinetic parameters (P=.95 for area under the plasma concentration-time curve from time 0 to infinity and P=.94 for oral clearance corrected for body weight). The formation of TXB2, reflecting cyclooxygenase type 1 activity, showed significant differences in the area above the effect-time curves (expressed as percent of baseline TXB2.h) between CYP2C9*1/*1 (10,190 +/- 2632) and either CYP2C9*1/*2 (19,255+/-1,291 [P=.00003]) or CYP2C9*1/*3 (18,241+/- 2397 [P=.00003]). The minimum serum TXB2 concentration, however, did not differ among the different genotypes (P=.32, ANOVA). CONCLUSION: Piroxicam's oral clearance was impaired and its inhibitory effect on cyclooxygenase 1 activity was increased in CYP2C9*1/*2 or CYP2C9*1/*3 individuals, as compared with CYP2C 9*1 homozygous individuals.