Polymorphic organic anion transporting polypeptide 1B1 is a major determinant of repaglinide pharmacokinetics

BACKGROUND AND OBJECTIVE: A large interindividual variability exists in the plasma concentrations of repaglinide. Our aim was to investigate possible associations between the pharmacokinetics of repaglinide and single nucleotide polymorphisms (SNPs) in the genes encoding for the drug transporters organic anion transporting polypeptide 1B1 (OATP1B1) (SLCO1B1 ) and P-glycoprotein ( MDR1 , ABCB1 ) and the drug-metabolizing enzymes cytochrome P450 (CYP) 2C8 and CYP3A5. METHODS: A total of 56 healthy volunteers ingested a single 0.25-mg dose of repaglinide. Plasma repaglinide and blood glucose concentrations were measured for up to 7 hours. All subjects were genotyped for the -11187G>A and 521T>C SNPs in SLCO1B1 and the 3435C>T and 2677G>T/A SNPs in ABCB1 , as well as for the CYP2C8*3 (416G>A, 1196A>G), CYP2C8*4 (792C>G), and CYP3A5*3 (6986A>G) alleles. RESULTS: The area under the plasma concentration-time curve from time 0 to infinity [AUC(0-infinity)] and peak concentration in plasma (Cmax) of repaglinide varied 16.9-fold and 10.7-fold, respectively, between individual subjects. Multiple regression analyses indicated that the SLCO1B1 521T>C SNP and the CYP2C8*3 allele were independent predictors of the AUC(0-infinity) and Cmax of repaglinide (adjusted multiple R2 = 45% and 36%, respectively). In subjects with the SLCO1B1 521CC genotype, the AUC(0-infinity) of repaglinide was 107% and 188% higher, respectively, than in subjects with the SLCO1B1 521TC or 521TT (reference) genotype (P < .0001). In subjects with the CYP2C8*1/*3 genotype, the AUC(0-infinity) and Cmax of repaglinide were 48% and 44% lower, respectively, than in those with the CYP2C8*1/*1 genotype (P < .05). The pharmacokinetics of repaglinide was not associated with the studied ABCB1 SNPs or the CYP3A5*3 allele. The elimination half-life of repaglinide was not associated with any SNP. Only the SLCO1B1 -11187GA genotype was significantly associated with an enhanced effect of repaglinide on blood glucose. CONCLUSIONS: Genetic polymorphism in SLCO1B1 is a major determinant of interindividual variability in the pharmacokinetics of repaglinide. The effect of SLCO1B1 polymorphism on the pharmacokinetics of repaglinide may be clinically important.     

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.     

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.     

Effect of CYP3A5*3 genotype on the pharmacokinetics and pharmacodynamics of amlodipine in healthy Korean subjects

BACKGROUND AND OBJECTIVE: 1,4-Dihydropyridine calcium channel blockers, including amlodipine, are mainly metabolized by cytochrome P450 (CYP) 3A. We investigated the effect of CYP3A5*3 genotype on the pharmacokinetics and pharmacodynamics of amlodipine in healthy Korean male subjects. METHODS: Forty healthy male participants were enrolled and genotyped for the CYP3A5*3 gene. Each subject ingested a 5-mg dose of amlodipine, and plasma amlodipine concentrations were measured for 144 hours after dosing. Blood pressure and pulse rate were also measured for pharmacodynamic analysis. RESULTS: Among the 40 volunteers, 24 were CYP3A5*3/*3 carriers and 16 were CYP3A5*1 carriers (CYP3A5*1/*1 in 2 and CYP3A5*1/*3 in 14). The difference in the oral clearance of amlodipine approached statistical significance between the 2 major genotype groups, with CYP3A5*1 carriers (27.0 +/- 8.2 L/h) showing 20% lower clearance than CYP3A5*3/*3 carriers (32.4 +/- 10.2 L/h) (P = .063). However, the mean area under the plasma concentration-time curve of amlodipine was 200.9 +/- 61.9 ng . h/mL for CYP3A5*1 carriers and 167.6 +/- 45.0 ng . h/mL for CYP3A5*3/*3 carriers (P = .029). Moreover, the peak plasma concentration was significantly higher in CYP3A5*1 carriers (3.8 +/- 1.1 ng/mL) than in CYP3A5*3/*3 carriers (3.1 +/- 0.8 ng/mL) (P = .037). Pharmacodynamically, blood pressure and pulse rate were not significantly different between the 2 groups. CONCLUSIONS: CYP3A5*3/*3 carriers exhibited lower plasma amlodipine concentrations than CYP3A5*1 carriers. These findings suggest that the polymorphic CYP3A5 gene affects the disposition of amlodipine and provides a plausible explanation for interindividual variability in amlodipine disposition.     

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.     

Effect of CYP3A5*3 genotype on the pharmacokinetics and pharmacodynamics of alprazolam in healthy subjects

OBJECTIVE: Our objective was to evaluate the effect of the CYP3A5 genotype on the pharmacokinetics and pharmacodynamics of alprazolam in healthy volunteers. METHODS: Nineteen healthy male volunteers were divided into 3 groups on the basis of the genetic polymorphism of CYP3A5. The groups comprised subjects with CYP3A5*1/*1 (n=5), CYP3A5*1/*3 (n=7), or CYP3A5*3/*3 (n=7). After a single oral 1-mg dose of alprazolam, plasma concentrations of alprazolam were measured up to 72 hours, together with assessment of psychomotor function by use of the Digit Symbol Substitution Test, according to CYP3A5 genotype. RESULTS: The area under the plasma concentration-time curve for alprazolam was significantly greater in subjects with CYP3A5*3/*3 (830.5+/-160.4 ng . h/mL [mean+/-SD]) than in those with CYP3A5*1/*1 (599.9+/-141.0 ng . h/mL) (P=.030). The oral clearance of alprazolam was also significantly different between the CYP3A5*1/*1 group (3.5+/-0.8 L/h) and CYP3A5*3/*3 group (2.5+/-0.5 L/h) (P=.036). Although a trend was noted for the area under the Digit Symbol Substitution Test score change-time curve (area under the effect curve) to be greater in subjects with CYP3A5*3/*3 (177.2+/-84.6) than in those with CYP3A5*1/*1 (107.5+/-44), the difference did not reach statistical significance (P=.148). CONCLUSIONS: The CYP3A5*3 genotype affects the disposition of alprazolam and thus influences the plasma levels of alprazolam.     

Relationship of paroxetine disposition to metoprolol metabolic ratio and CYP2D6*10 genotype of Korean subjects

OBJECTIVE: To evaluate the relationship between the metabolic ratio (MR) of metoprolol, CYP2D6*10B genotype, and the disposition of paroxetine in Korean subjects. METHODS: A single 40-mg dose of paroxetine was administered orally to one poor metabolizer and 15 healthy subjects recruited from 223 Korean extensive metabolizers whose phenotypes were predetermined by use of the metoprolol MR. Genotypes were determined by allele-specific polymerase chain reaction and the GeneChip microarray technique. Pharmacokinetic parameters were estimated from plasma concentrations of paroxetine for more than 240 hours after the oral dose. RESULTS: The oral clearance and area under the plasma concentration versus time curve (AUC) of paroxetine were best described by a nonlinear relationship with metoprolol MR at correlation coefficients of 0.82 and 0.91, respectively (P < .05). Nine extensive metabolizer who were either homozygous or heterozygous for CYP2D6*10B had significantly lower oral clearance values of paroxetine than six extensive metabolizers with CYP2D6*1/*1. The AUC of paroxetine in subjects who were homozygous for CYP2D6*10B (666.4 +/- 169.4 ng/mL x h) was significantly greater than that of subjects who were homozygous for the wild type (194.5 +/- 55.9 ng/mL x h). Unexpectedly, the average AUC of subjects who were heterozygous for CYP2D6*10B was greater with wide variation (789.8 +/- 816.9 ng/mL x h) than that of subjects who were homozygous CYP2D6*10B/*10B mainly because of two atypical subjects whose metoprolol MR was not associated with the CYP2D6*10B genotype and who showed greater AUC and lower oral clearance than subjects with homozygous CYP2D6*10B. CONCLUSIONS: The CYP2D6 activity measured by metoprolol MR was a strong predictor of paroxetine disposition in Korean extensive metabolizers. In general, the extensive metabolizers with the CYP2D6*10B allele seemed to have higher plasma concentrations of paroxetine than extensive metabolizers with the wild-type CYP2D6 genotype. However, quantitative prediction of paroxetine disposition from the CYP2D6*10B genotype alone was not perfect because several Korean extensive metabolizers had metoprolol MRs that were not associated with the genotype.     

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.     

Effect of OATP1B1 (SLCO1B1) variant alleles on the pharmacokinetics of pitavastatin in healthy volunteers

BACKGROUND: Pitavastatin is a potent, newly developed 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor for the treatment of hyperlipidemia. We characterized the effects of organic anion transporting polypeptide 1 B 1 (OATP 1 B 1) alleles *1a, *1b, and *15 on the pharmacokinetics of pitavastatin. METHODS: Twenty-four healthy Korean volunteers who had previously participated in a pharmacokinetic study of pitavastatin (single oral dose, 1--8 mg) were further investigated. Subjects were grouped according to OATP 1 B 1 genotype. Dose-normalized area under the plasma concentration-time curve (AUC) and peak plasma concentration (C(max)) values were analyzed, because different dosages were administered to subjects, whereas the pharmacokinetics showed linear characteristics. RESULTS: Dose-normalized pitavastatin AUCs for *1b/*1b (group 1), *1a/*1a or *1a/*1b (group 2), and *1a/*15 or *1b/*15 (group 3) were 38.8+/-13.3, 54.4 +/-12.4, and 68.1+/-6.3 ng.h.mL(-1).mg(-1) (mean+/-SD), respectively, with significant differences between all 3 groups (P=.008) and between subjects carrying and those not carrying the *15 allele (P = .004). Dose-normalized pitavastatin C(max) values were 13.2+/- 3.3, 18.2+/-5.7, and 29.4+/- 9.6 ng.mL(-1).mg(-1) in groups 1, 2, and 3, respectively, and also showed significant differences (P=.003) in a manner similar to that shown by AUC. No significant differences were found between the genotype groups in terms of dose-normalized AUC or C(max) values of pitavastatin lactone. CONCLUSION: OATP 1 B 1 variant haplotypes were found to have a significant effect on the pharmacokinetics of pitavastatin. These results suggest that the *15 allele is associated with decreased pitavastatin uptake from blood into hepatocytes and that OATP 1 B 1 genetic polymorphisms have no effect on the pharmacokinetics of pitavastatin lactone.     

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.     

Glyburide and glimepiride pharmacokinetics in subjects with different CYP2C9 genotypes

OBJECTIVES: Our objective was to investigate the effects of genetic polymorphisms of cytochrome P450 (CYP) 2C9 on the pharmacokinetics of glyburide (INN, glibenclamide) and glimepiride, two widely used sulfonylurea antidiabetic drugs. METHODS: We conducted CYP2C9 genotyping for 29 healthy volunteers who had participated in our previous pharmacokinetic studies on glyburide or glimepiride. RESULTS: There were 17 subjects (59%) with the CYP2C9*1/*1 (wild-type) genotype, 8 (28%) with the CYP2C9*1/*2 genotype, 3 (10%) with the CYP2C9*1/*3 genotype, and 1 (3%) with the CYP2C9*2/*3 genotype. The pharmacokinetics of glyburide or glimepiride were not significantly changed among subjects with the CYP2C9*1/*2 genotype. However, in individuals heterozygous for the CYP2C9*3 allele, the median total area under the plasma concentration-time curve of glyburide (n = 2) was 280% (P < or = .05) and that of glimepiride (n = 3) was 267% (P < or = .01) of the respective values in subjects with the CYP2C9*1/*1 genotype (n = 5 and n = 12, respectively). Blood glucose responses to glyburide and glimepiride were not significantly affected by the CYP2C9 genotype. CONCLUSIONS: Genetic polymorphisms of CYP2C9 markedly affect the pharmacokinetics of both glyburide and glimepiride. The influence of the CYP2C9*3 variant allele on glyburide and glimepiride pharmacokinetics may be clinically significant.     

Pharmacokinetics of the new proton pump inhibitor ilaprazole in Chinese healthy subjects in relation to CYP3A5 and CYP2C19 genotypes

BACKGROUND: PPIs are widely used in peptic diseases, and this paper is to investigate the kinetic characteristics of a new PPI ilaprazole in Chinese healthy subjects and the association with CYP3A5 and CYP2C19 polymorphisms. METHODS: 21 subjects were selected and treated with 10mg ilaprazole according to their CYP3A5*3 genotypes (including 7 of CYP3A5*1/*1, 7 of *1/*3, and 7 of *3/*3). The plasma concentrations of ilaprazole and its metabolites were monitored by LC-MS/MS method. RESULTS: The C(max), AUC((0-6)), AUC((0-48)) and AUC((0-infinity)) of ilaprazole were all significantly different across the 3 CYP3A5 genotypes (including 4 of CYP3A5*1/*1, 4 of *1/*3, 3 of *3/*3; P<0.05) in CYP2C19 wild-type subjects (CYP2C19 wt/wts), similar variety of C(max) and AUC((0-6)) among CYP3A5 genotypes (including 3 of CYP3A5*1/*1, 3 of *1/*3, 4 of *3/*3; P<0.05) were also observed in CYP2C19 heterozygous subjects (CYP2C19 wt/mts). The sulfoxidation metabolic index (measure of collective CYP3A activity) indicates that the CYP3A5*1/*1, (high-expressers), *1/*3, (low-expressers), and *3/*3 (no-expressers) groups have medium, lowest and highest activities on ilaprazole metabolism, inconsistent with genotype-based CYP3A5 enzymatic activity. Further analysis showed no correlation between ilaprazole metabolism and CYP2C19 genotypes, evidenced by that the AUC((0-infinity)) of ilaprazole from either CYP3A5*1/*1 or CYP3A5*1/*3 groups was much higher in CYP2C19 wt/wts (n=4) than that in CYP2C19 wt/mts (n=3) (P<0.001), but the C(max) and AUC((0-6)) of ilaprazole from CYP3A5*3/*3 groups, were significantly lower in CYP2C19 wt/wts (n=3) compared to CYP2C19 wt/mts (n=4) (P<0.01). CONCLUSIONS: There was no demonstrated relationship between ilaprazole metabolism and CYP3A5 polymorphisms.     

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.     

Evaluation of potential losartan-phenytoin drug interactions in healthy volunteers

BACKGROUND: Phenytoin, a cytochrome P450 (CYP) 2C9 substrate, has a narrow therapeutic index and nonlinear pharmacokinetics. Therefore there is the potential for significant concentration-related adverse effects when phenytoin is coadministered with other CYP2C9 substrates. Losartan, an antihypertensive agent, is also a substrate for CYP2C9. OBJECTIVE: Our objective was to assess the effects of losartan on the pharmacokinetics of phenytoin and the effects of phenytoin on the pharmacokinetics of losartan in a healthy population of volunteers. METHODS: A prospective, randomized, 3-period crossover study was conducted in 16 healthy volunteers with phenytoin alone, phenytoin in combination with losartan, and losartan alone. Each treatment was given for 10 days with a 3-week washout period between treatments. On day 10, plasma concentrations of phenytoin and plasma and urine concentrations of losartan and its active carboxylic-acid metabolite E3174 were measured to determine steady-state pharmacokinetic parameters. RESULTS: Coadministration of losartan had no effect on the pharmacokinetics of phenytoin. Coadministration of phenytoin increased the mean area under the concentration-time curve from time zero to 24 hours [AUC(0-24)] of losartan by 17% (355 +/- 220 ng x h/mL versus 427 +/- 177 ng x h/mL; P =.1), but this difference was not statistically significant. In the 14 CYP2C9*1/*1 subjects, the mean AUC(0-24) of losartan was increased by 29% (284 +/- 84 ng x h/mL versus 402 +/- 128 ng x h/mL; P =.008). Coadministration of phenytoin significantly reduced the AUC(0-24) of E3174 by 63% (1254 +/- 256 ng x h/mL versus 466 +/- 174 ng x h/mL; P =.0001) and the formation clearance of losartan to E3174 (1.91 +/- 0.8 mL/h per kilogram versus 0.62 +/- 0.4 mL/h per kilogram; P =.0001). CONCLUSIONS: Losartan, a CYP2C9 substrate, had no effect on the pharmacokinetics of phenytoin. However, phenytoin inhibited the CYP2C9-mediated conversion of losartan to E3174.     

Acenocoumarol pharmacokinetics in relation to cytochrome P450 2C9 genotype

BACKGROUND AND OBJECTIVES: Cytochrome P450 (CYP) 2C9 is one of the major CYP enzymes involved in the biotransformation of drugs, among others, the oral anticoagulant acenocoumarol. The enzyme has several polymorphisms, with the CYP2C9*2 and CYP2C9*3 variants most commonly present in white patients. Patients with the CYP2C9*3 variant are known to require a lower maintenance dose of racemic acenocoumarol. We investigated the impact of the polymorphisms CYP2C9*2 and CYP2C9*3 on the pharmacokinetics of R- and S-acenocoumarol. METHODS AND RESULTS: In the first study 26 healthy volunteers with the genotype *1/*1 (n = 9), *1/*2 (n = 7), *1/*3 (n = 6), *2/*3 (n = 3), and *2/*2 (n = 1) were given 8 mg of racemic acenocoumarol as a single oral dose. Plasma R- and S-acenocoumarol concentrations were assayed at 4, 7, and 24 hours. Mean plasma S-acenocoumarol concentrations at 7 hours were higher in subjects with a variant allele; the differences were significant (P =.01) for the *1/*3 and *2/*3 genotypes. In the second study, the oral pharmacokinetics of acenocoumarol was investigated in 6 subjects (*1/*1 [n = 3] and *1/*3 [n = 3]). The mean oral clearance of S-acenocoumarol was 45% lower in the CYP2C9*1/*3 genotypes (10.9 +/- 3.0 L/h versus 19.8 +/- 3.1 L/h, P =.02). Plasma half-life was prolonged from 1.0 +/- 0.2 hours to 2.0 +/- 0.7 hours (P =.09). R-acenocoumarol pharmacokinetics did not differ between the genotypes. There was no difference in mean international normalized ratio at 24 hours, which was 1.2 in both groups. In vitro enzyme kinetics showed reduced (85%) intrinsic activity of the *3 enzyme to catalyze the hydroxylations of S-acenocoumarol. The lower activity resulted from higher Michaelis-Menten constant (2-fold) and lower maximum rate of metabolism by an enzyme-mediated reaction (by 70%). The activity of the *2 enzyme was 50% of the wild-type one. CONCLUSION: The results show S-acenocoumarol pharmacokinetics to be dependent on CYP2C9 polymorphism. In particular, the presence of the CYP2C9*3 allele impairs oral clearance of the coumarin.     

Potent cytochrome P450 2C19 genotype-related interaction between voriconazole and the cytochrome P450 3A4 inhibitor ritonavir

OBJECTIVES: Cytochrome P450 (CYP) 2C19 and CYP3A4 are the major enzymes responsible for voriconazole elimination. Because the activity of CYP2C19 is under genetic control, the extent of inhibition with a CYP3A4 inhibitor was expected to be modulated by the CYP2C19 metabolizer status. This study thus assessed the effect of the potent CYP3A4 inhibitor ritonavir after short-term administration on voriconazole pharmacokinetics in extensive metabolizers (EMs) and poor metabolizers (PMs) of CYP2C19. METHODS: In a randomized, placebo-controlled crossover study, 20 healthy participants who were stratified according to CYP2C19 genotype received oral ritonavir (300 mg twice daily) or placebo for 2 days. Together with the first ritonavir or placebo dose, a single oral dose of 400 mg voriconazole was administered. Voriconazole was determined in plasma and urine by liquid chromatography-mass spectrometry, and pharmacokinetic parameters were estimated by noncompartmental analysis. RESULTS: When given alone, the apparent oral clearance of voriconazole after single oral dosing was 26%+/-16% (P > .05) lower in CYP2C19*1/*2 individuals and 66%+/-14% (P < .01) lower in CYP2C19 PMs. The addition of ritonavir caused a major reduction in voriconazole apparent oral clearance (354+/-173 mL/min versus 202+/-139 mL/min, P = .0001). This reduction occurred in all CYP2C19 genotypes (463+/-168 mL/min versus 305+/-112 mL/min [P = .023] for *1/*1, 343+/-127 mL/min versus 190+/-93 mL/min [P = .008] for *1/*2, and 158+/-54 mL/min versus 22+/-11 mL/min for *2/*2) and is probably caused by inhibition of CYP3A4-mediated voriconazole metabolism. CONCLUSIONS: Coadministration of a potent CYP3A4 inhibitor leads to a higher and prolonged exposure with voriconazole that might increase the risk of the development of adverse drug reactions on a short-term basis, particularly in CYP2C19 PM patients.     

Relationship of P450 2C9 genetic polymorphisms in Chinese and the pharmacokinetics of tolbutamide

AIM: To study the relationship between P450 2C9 genetic polymorphisms and the pharmacokinetics of tolbutamide in Chinese subjects. METHODS: P450 2C9 genotype was determined by oligonucleotide microarray. Using tolbutamide as a probe of P450 2C9 activity, P450 2C9 phenotype in 20 healthy individuals expressing the P450 2C9*1/*1, *1/*3 and *3/*3 genotypes were evaluated. After administration of 500 mg tolbutamide, plasma and urine samples were collected from each subject over a 24-h period. The tolbutamide and its metabolites' concentrations in human plasma and urine were determined by solid-phase extraction and HPLC. RESULTS: Tolbutamide AUC0-->infinity increased by 20 and 116%, and T(1/2) increased by 60 and 813%, respectively, in subjects expressing the P4502C9*1/*3 and *3/*3 genotypes compared with *1/*1 subjects. Reductions in tolbutamide oral clearance (68 and 11%) and formation clearance (39 and 3%) were detected in the *1/*3 and *3/*3 individuals, respectively, compared with */*1 subjects. CONCLUSION: The P450 2C9 activity was significantly reduced in *1 heterozygotes compared with *1 homozygotes, and the metabolism of tolbutamide was more severely impaired in *3/*3 individuals compared with those expressing *1/*3. Using tolbutamide as a P450 2C9 probe, P450 2C9 genotype was the major determinant of P450 2C9 phenotype.     

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.     

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.