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Objective: To investigate pharmacokinetic and pharmacodynamic factors associated with population differences in warfarin doses needed to achieve anticoagulation, in particular the possible involvement of genetic variability in vitamin K epoxide reductase (VKOR) and CYP2C9., Methods: Warfarin maintenance dose, unbound plasma S-warfarin concentration [Cu(S)] and INR were determined in 157 Caucasians, 172 Japanese, and 36 African-Americans stably anticoagulated patients. In a subset (n = 166), fully carboxylated plasma normal prothrombin levels (NPT) were also measured. Genotyping for seven CYP2C9 (CYP2C9*1 through 6 and *11) and seven VKORC1 variants were performed in 115 Caucasians and 64 Japanese patients and 66 healthy African-Americans. Multivariate analysis was performed to identify covariates associated with warfarin requirement., Results: The relationship between NPT and Cu(S) indicated Japanese are more susceptible to inhibition of NPT production by S-warfarin than the other two populations. VKORC1 1173 C > T had a greater frequency in Japanese (89.1%) than Caucasians (42.2%) and African-Americans (8.6%). CYP2C9 variants with reduced metabolizing ability were less frequent in Japanese compared to the other two populations. The median warfarin dose was significantly higher in Caucasians than Japanese patients (5.5 versus 3.5 mg/day), however, when matched for CYP2C9*1 homozygosity, no difference in dose was observed between VKORC1 genotype-matched groups. Furthermore, VKORC1 1173C > T and CYP2C9 (*2/*3/*11) genotypes, age and weight were identified as independent covariates contributing to interpatient variability in warfarin dosage., Conclusions: Both VKORC1 and CYP2C9 polymorphisms contribute to inter-population difference in warfarin doses among the three populations, but their contribution to intra-population variability may differ within each population.

To study whether chronic liver disease (CLD) and genetic polymorphism affect the hepatic activity of cytochrome P450 (CYP) isoforms, we compared in vivo CYP2C19 and CYP3A activities using 3-hour omeprazole hydroxylation index (plasma concentration ratio of omeprazole to its 5-hydroxylated metabolite; a higher index indicates lower CYP2C19 activity) and partial formation clearance of cortisol to 6beta-hydroxycortisol (CL(cortisol-->6beta-HC)) in 31 CLD patients (9 with chronic hepatitis; 22 with cirrhosis comprising 20 Child-Pugh type A, 1 type B, and 1 type C) and 30 healthy subjects with different CYP2C19 genotypes. The mean (+/-SEM) omeprazole hydroxylation index in CLD patients with homozygous extensive metabolizer (EM) genotype (*1/*1, n = 8), heterozyous EM (*1/*2, n = 11; *1/*3, n = 6) genotypes and poor metabolizer (PM) genotypes (*2/*2, n = 3; *3/*3, n = 3) were 17.15 +/- 2.12, 20.02 +/- 2.63, and 26.04 +/- 3.15, respectively, which were significantly higher compared with control subjects with the corresponding CYP2C19 genotypes (0.81 +/- 0.09, 1.55 +/- 0.20, and 15.5 +/- 1.52). CLD patients with PM genotype had significantly (P < .05) higher omeprazole hydroxylation indexes than did those with homozygous EM genotype, and those with heterozygous EM genotypes had intermediate values. The mean CL(cortisol-->6beta-HC) decreased significantly (P < .001) in CLD patients compared with control subjects (1.19 +/- 0.12 versus 2.26 +/- 0.24 mL/min). Multiple regression analysis showed that CLD, serum albumin level, and CYP2C19 genotype correlated significantly (P < .05) with the omeprazole hydroxylation index, whereas no significant correlation was observed between CL(cortisol-->6beta-HC) and other variables, except CLD. Because CLD and genetic polymorphism of CYP2C19 act additively to reduce CYP2C19 activity, genotyping these patients may be of value in averting adverse reactions of drugs that depend on CYP2C19 for elimination.

White and Japanese patients require different warfarin dosages to achieve therapeutic anticoagulation, but this can be only partly explained by genetic variability in the coding region of CYP2C9-a critical enzyme in the drug's metabolism. Accordingly, analysis of the -2.1-kb 5'-flanking region of CYP2C9 was undertaken in 22 white and 38 Japanese patients whose unbound oral clearance of S-warfarin had been previously determined. Thirteen single nucleotide polymorphisms (SNPs) were identified, some of which were in linkage disequilibrium with functionally defective coding region variants. Those 5'-flanking patterns linked with at least one CYP2C9*3 allele or CYP2C9*2/*3 were associated with reduced CYP2C9 activity and warfarin dose. Japanese patients possessing the wild-type promoter and coding sequences had significantly (P <.01) greater CYP2C9 activity than white patients with the corresponding genotype. In conclusion, either unidentified polymorphisms further upstream in the promoter region or environmental factor(s) account for the differences in the warfarin doses between whites and Japanese.

The Chinese herbal medicine sho-saiko-to is a mixture of seven herbal components (Bupleurum root, Pinellia tuber, Scutellaria root, Jujube fruit, Ginseng root, Glycyrrhiza root and Ginger rhizome) that is widely administered to patients with chronic hepatitis in Japan. We assessed the effects of sho-saiko-to on the activity of cytochrome P450 (CYP) 1A2, CYP3A and xanthine oxidase (XO) in man. Twenty-six healthy subjects were studied to evaluate their baseline activity of CYP1A2 and XO by the respective urinary metabolic ratios of an 8-h urine sample after an oral 150-mg dose of caffeine and of CYP3A by a urinary excretion ratio of 6beta-hydroxycortisol (6beta-HC) to free cortisol (FC). Thereafter, the subjects received a twice-daily 2.5-g dose of sho-saiko-to for five days, and underwent the caffeine test on day 1 and day 5. The mean activity of CYP1A2 decreased by 16% on both day 1 and day 5 compared with the baseline (P=0.001). The mean activity of XO also significantly decreased by 25% on day 1 and 20% on day 5 (P<0.0001) compared with the baseline value. The activity of CYP3A tended to be lower on day 5 than the baseline (P=0.146). It is concluded that sho-saiko-to reduces CYP1A2 and XO activity in man.

Objective: Our objective was to investigate population differences in the metabolic activity of cytochrome P450 (CYP) 2C9 between genotypically matched Caucasian and Japanese patients by using the unbound oral clearance of S-warfarin as an in vivo phenotypic trait measure., Methods: Ninety Japanese and 47 Caucasian patients receiving maintenance warfarin therapy were studied. Steady-state plasma unbound concentrations of S-warfarin were measured by a chiral HPLC method coupled with an ultrafiltration technique, and unbound oral clearance for S-warfarin was estimated. By combining plasma unbound concentrations of S-warfarin with the urinary excretion rates of S-7-hydroxywarfarin, the formation clearance of S-7-hydroxywarfarin was also determined. Genotyping of CYP2C9 was performed for 6 distinct alleles (CYP2C9*1, CYP2C9*2, CYP2C9*3, CYP2C9*4, CYP2C9*5, and a T/C transition in intron 2)., Results: The frequency distribution of unbound oral clearance for S-warfarin obtained from Japanese patients was shifted toward higher values as compared with that in Caucasian patients. Japanese patients had lower allelic frequencies for the 5 variants than Caucasian patients. When interpopulation comparisons of CYP2C9 activity were made for genotype-matched subjects, Japanese patients with the homozygous CYP2C9*1 (wild-type) genotype (n = 85) had significantly (P <.01) greater median values for unbound oral clearance and formation clearance than Caucasian patients with the corresponding genotype (n = 26), 10.4 mL x min(-1) x kg(-1) versus 4.25 mL x min(-1) x kg(-1) and 0.015 mL x min(-1) x kg(-1) versus 0.010 mL x min(-1) x kg(-1), respectively. In addition, Japanese patients heterozygous for the CYP2C9*3 genotype (n = 4) showed a significantly (P <.05) reduced unbound oral clearance for S-warfarin, by 63%, as compared with Japanese patients possessing the homozygous CYP2C9*1 genotype. By contrast, in Caucasian patients, no significant differences were observed in this parameter between CYP2C9(*)1 homozygous subjects and those with heterozygous CYP2C9(*)2 or CYP2C9(*)3 genotypes., Conclusions: These findings indicate that population differences in the frequencies of known variant CYP2C9 alleles account only in part for the variability observed in in vivo CYP2C9 activity in different populations. In addition, a gene-dose effect of defective CYP2C9 alleles on the in vivo CYP2C9 activity is evident in Japanese patients but not in Caucasian patients. Further studies are required to identify currently unknown factor(s) (eg, transcriptional regulation) responsible for the large intrapopulation and interpopulation variability in CYP2C9 activity.

Objective: A 7-day triple therapy with lansoprazole, amoxicillin (INN, amoxicilline), and clarithromycin is widely used for eradication of Helicobacter pylori. Because clarithromycin is a potent inhibitor of cytochrome P450 (CYP) 3A, we investigated whether the standard triple therapy with clarithromycin would elicit clinically relevant CYP3A inhibition and alter CYP3A-mediated lansoprazole disposition in H pylori-positive patients., Methods: Twenty H pylori-positive patients with peptic ulcer disease were randomly assigned to 2 groups: One group received 200 mg clarithromycin, 30 mg lansoprazole, and 750 mg amoxicillin at 8 am and 8 pm for 7 days; the other group received 400 mg clarithromycin, 30 mg lansoprazole, and 750 mg amoxicillin at 8 am and 8 pm for 7 days. Ten healthy control subjects received 30 mg lansoprazole and 750 mg amoxicillin at 8 am and 8 pm for 7 days but did not receive clarithromycin. Urine samples were collected for 3 hours (from 8 am to 11 am) for urinary 6beta-hydroxycortisol and cortisol assay, and midpoint (at 9:30 am) plasma samples for cortisol assay were obtained from all participants before the drug therapy (day 0) and on day 7. In vivo CYP3A activity was assessed by the partial cortisol clearance by means of the formation of 6beta-hydroxycortisol (CL(cortisol-->6beta-hydroxycortisol)) and the urinary 6beta-hydroxycortisol/cortisol ratio. Additional plasma samples for lansoprazole, 5-hydroxylansoprazole, and lansoprazole sulfone assay were obtained at 11 am on day 7., Results: The groups of patients given 400 and 800 mg/day clarithromycin for H pylori eradication therapy showed 39% (from 2.20 +/- 1.29 to 1.35 +/- 0.88 mL/min [day 0 versus 7, mean +/- SD]; P <.05) and 68% (2.40 +/- 1.22 to 0.76 +/- 0.51 mL/min; P <.05) reductions in CL(cortisol-->6beta-hydroxycortisol), respectively. In contrast, the control subjects given lansoprazole and amoxicillin without clarithromycin showed no significant changes in CL(cortisol-->6beta-hydroxycortisol). The urinary 6beta-hydroxycortisol/cortisol ratio also decreased significantly (P <.05) in the patient groups but not in the control subjects. The mean 3-hour plasma lansoprazole levels elevated in proportion to the doses of clarithromycin: 385 +/- 338 ng/mL for the control subjects, 696 +/- 797 ng/mL for the H pylori-positive patients given 400 mg/day clarithromycin, and 947 +/- 806 ng/mL for the H pylori-positive patients given 800 mg/day clarithromycin (P <.05 versus the control subjects). No significant differences were observed among the groups in the mean plasma ratios of 5-hydroxylansoprazole or lansoprazole sulfone to lansoprazole., Conclusions: The 7-day H pylori eradication therapy with clarithromycin, amoxicillin, and lansoprazole may elicit substantial inhibition of in vivo CYP3A activity. Although resultant elevations in plasma lansoprazole concentrations may be beneficial for H pylori eradication, caution must be exercised for possible drug interaction with a concomitantly administered CYP3A substrate (s) in patients undergoing H pylori eradication therapy with clarithromycin, amoxicillin, and lansoprazole.