The Effect Of Liuwei Dihuangwan On Human Cytochrome P450 Activity

Objective: To investigate the effect of Liuwei Dihuangwan on cytochrome P450 activitiy in healthy subjects.Methods: The potential of Liuwei Dihuangwan to alter the activity of cytochrome P450 was evaluated in this study, employing simultaneous oral administration of caffeine, omeprazole, dextromethorphan and intravenous administration of midazolam to probe the metabolic activities of CYP1A2,CYP2C19, CYP2D6 and CYP3A4 isozymes, respectively. Genotypes were determined by PCR-RFLP. Twelve volunteers including six homozygous extensive metabolizers and six poor metabolizers for CYP2C19 from two hundred and ninety seven volunteers participated in the study. An open, randomized, two-way crossover design was performed. In each phase, the volunteers divided into two groups received placebo or Liuwei Dihuangwan(HUNAN JIUZHITANG CO.,LTD, 20060840) 12 pills, 2 times daily for 14 days. All the subjects were administered the following drugs orally on the fifteenth day: caffeine 100 mg, omeprazole 30 mg, dextromethorphan hydrobromide 30 mg and inravenously midazolam 0.025 mg/kg at 8:00 am after fasting overnight. Blood samples during 0～24 hours and urine during 0～12 hours were collected after dosing. There is a two-week washout period between two phases. The concentrations of caffeine and its metabolite paraxanthine were detected by HPLC method, and the concentrations of omeprazole, dextromethorphan, midazolam and their metabolites were detected by HPLC-MS/MS method, respectively, the pharmacokinetics parameters of individual probe drug and its metabolites between different treatment phases and among different genotype groups were compared, using the plasma paraxanthine / caffeine AUC ratio as the index of CYP1A2 activity, the plasma 5-hydroxyomeprazole/omeprazole AUC ratio as the index of CYP2C19 activity, the urinary metabolic ratio of dextrorphan/ dextromethorphan as the index of CYP2D6 activity and the 1-OH midazolam/midazolam AUC ratio as the index of CYP3A4 activity.Results: Before and after administration of Liuwei Dihuangwan, the paraxanthine/caffeine AUC_0-24 ratios were 0.55±0.14 and 0.63±0.16, the paraxanthine/caffeine AUC_0-8 ratios were 0.67±0.23 and 0.77±0.20, the 5-hydroxyomeprazole/omeprazole AUC_0-12 ratios were 1.33±1.69 and 1.18±0.95, and the 5-hydroxyomeprazole/omeprazole AUC0-8 ratios were 1.06±1.30 and 0.95±0.90, respectively. The urinary metabolic ratio of dextrorphan/dextromethorphan were 0.47±0.43 and 0.25±0.13, respectively. The 1-OH midazolarn/midazolam AUC_0-12 ratios of CYP3A4 activities were 0.31±0.10 and 0.37±0.14, and the 1-OH midazolam/midazolam AUC_0-8 ratios were 0.35±0.089 and 0.40±0.15, respectively. There were nod significant difference between the corresponding indices of the enzyme activities before and after Liuwei Dihuangwan treatment.Conclusions: Liuwei Dihuangwan did not alter significant the activity of CYP1A2, CYP2C19, CYP2D6 and CYP3A4 and is unlikely to participate in drug interactions involving medications predominantly metabolized by these four enzymes.