No abstract

1. Quercetin, one of the most abundant natural flavonoids, has been reported to modulate the activity of several drug-metabolising enzymes. The aim of the present study was to investigate the effects of quercetin on cytochrome P450 (CYP) 1A2, CYP2A6, N-acetyltransferase (NAT2) and xanthine oxidase (XO) activity in healthy volunteers using caffeine as a probe drug. 2. Twelve unrelated, healthy volunteers were recruited to the study. There were two phases to the study; in the first phase, each subject was given a single oral dose of caffeine (one 100 mg capsule) with 150 mL water; in the second phase, each subject was give a 500 mg quercetin capsule once daily for 13 continuous days and was coadministered a 100 mg caffeine capsule on the 13th day. Urinary caffeine metabolite ratios were used as indicators of the activity of CYP1A2, CYP2A6, NAT2 and XO. The pharmacokinetics of caffeine and its metabolites were determined by HPLC. 3. In the quercetin-treated group, CYP1A2 activity was decreased by 10.4% (95% confidence interval (CI), 1.1-29.8%; P = 0.039), whereas increases were observed in CYP2A6 (by 25.3%; 95% CI, 6.2-34.5%; P = 0.002), NAT2 (by 88.7%; 95% CI, 7.1-160.2%; P = 0.010) and XO activity (by 15.0%; 95% CI, 1.6-21.6%; P = 0.007). Plasma C(max) and the AUC((0-24 h)) of 1,7-dimethylxanthine were decreased by 17.2% (95% CI, 6.4-28.0%; P = 0.024) and 16.2% (95% CI, 3.9-28.5%; P = 0.032), respectively. The urinary excretion of 1,7-dimethylxanthine and 1-methylxanthine was significantly decreased by 32.4% (95% CI, 2.5-62.1%; P = 0.036) and 156.1% (95% CI, 53.3-258.9%; P = 0.004), respectively. The urinary excretion of 1,7-dimethylurate and 1-methylurate was increased by 82.9% (95% CI, 56.0-165.4%; P = 0.030) and 97.8% (95% CI, 12.1-183.5%; P = 0.029), respectively. No changes were observed in the urinary excretion of caffeine and 5-acetylamino-6-formylamino-3-methyluracil between the two study phases. 4. The results of the present study indicate that quercetin inhibits CYP1A2 function, but enhances CYP2A6, NAT2 and XO activity. Simultaneously, some pharmacokinetic parameters relating to 1,7-dimethylxanthine were affected by quercetin. Thus, we conclude that quercetin affects CYP1A2, CYP2A6, NAT2 and XO activity in vivo.

This study explores the impact of clopidogrel on the pharmacokinetics of omeprazole related to CYP2C19 genetic polymorphisms. Twelve healthy volunteers (6 CYP2C19*1/*1, 5 CYP2C19*2/*2, and 1 CYP2C19*2/*3) are enrolled in a 2-phase randomized crossover trial. In each phase, the volunteers are administered a single oral dose of omeprazole 40 mg after pretreatment of either placebo or clopidogrel (300 mg on the first day and then 75 mg once daily for 3 consecutive days). Plasma concentrations of omeprazole and its metabolites are quantified by high-performance liquid chromatography with UV detection. After clopidogrel treatment, the AUC(0-infinity) of omeprazole increases by 30.02% +/- 18.03% (P = .004) and that of 5-hydroxyomeprazole decreases by 24.30% +/- 11.66% (P = .032) in CYP2C19*1/*1. The AUC(0-infinity) ratios of omeprazole to 5-hydroxyomeprazole increase by 74.98% +/- 35.48% (P = .001) and those of omeprazole to omeprazole sulfone do not change significantly (P = .832) in CYP2C19*1/*1. No significant alteration is observed in CYP2C19*2/*2 or *3. Clopidogrel inhibits CYP2C19-dependent hydroxylation of omeprazole in CYP2C19*1/*1 and has no impact on CYP3A4-catalyzed sulfoxidation of omeprazole.

The objective of this study was to investigate the interaction between glycyrrhizin and omeprazole and observe the effects of glycyrrhizin on CYP2C19 and CYP3A4 activities in healthy Chinese male volunteers with different CYP2C19 genotypes. Eighteen healthy subjects (six CYP2C19*1/*1, five CYP2C19*1/*2, one CYP2C19*1/*3, five CYP2C19*2/*2 and one CYP2C19*2/*3) were enrolled in a two-phase randomized crossover trial. In each phase, all subjects received placebo or glycyrrhizin salt tablet 150 mg twice daily for 14 consecutive days. The pharmacokinetics of omeprazole (20 mg orally on day 15) was determined for up to 12 h following administration by high-performance liquid chromatography. After 14-day treatment of glycyrrhizin, plasma omeprazole significantly decreased, and those of omeprazole sulfone significantly increased. However, plasma concenetrations of 5-hydroxyomeprazole did not significantly change. The ratio of AUC(0-infinity) of omeprazole to omeprazole sulfone decreased by 43.93% + or - 13.56% (p = 0.009) in CYP2C19*1/*1, 44.85% + or - 14.84% (p = 0.002) in CYP2C19*1/*2 or *3 and 36.16% + or - 7.52% (p < 0.001) in CYP2C19*2/*2 or *3 while those of omeprazole to 5-hydroxyomeprazole did not change significantly in all three genotypes. No significant differences in glycyrrhizin response were found among CYP2C19 genotypes. Glycyrrhizin induces CYP3A4-catalyzed sulfoxidation of omeprazole and leads to decreased omeprazole plasma concentrations, but has no significant impact on CYP2C19-dependent hydroxylation of omeprazole.