Studies Of Drug Interactions Related To Botanical Ployphenolic Curcumin Etc.

Botanicals are widely used in resent years, and several common herbal medicines have been proved to be beneficial to health. Although herbal products are often regard as natural and safe, adverse events caused by herb-drug interactions are growing concern over the last several years for herbal therapies escalating. The safety of potential herb-drug interaction in patients with chronic disease or for drugs with narrow therapeutic indices has begun to draw more and more attention.This paper concerns the effect of two polyphenol, which are curcumin and puerarin on drug-metabolizing enzymes, in order to predict possible herb-drug interaction. In vivo and in vitro studies were conducted of the two botanicals, and the data of our study provides important information for safety and rationality of clinical drug combination.Curcumin and puerarin are widely used in clinical. With the development of modern pharmaceutical technology, curcumin and puerarin have been further developed as many formulations for the treatment of disease. Though, many reaches have performed on the pharmacology and pharmacokinetics of curcumin and puerarin, this study focus on their potential drug interactions mediated by P450 enzyme in vitro and in vivo.1. In this paper, the inhibition of main subfamily of P450 enzymes by curcumin or puerarin was studied in human liver microsomal model. Phenacetin(CYPlA2), nifedipine(CYP3A4), tolbutamide(CYP2C9), chlorzoxazone(CYP2E1) and dextromethorphan (CYP2D6) were incubated as probes, and the metabolites, acetaminophen,4-hydroxyl-tolbutamide, dehydro-nifedipine, o-demethyl-dextromethorphan and 6-hydroxyl-chlorzoxazone were determined by LC-MS/MS, and the CYP activities were measured by the metabolites production. The results were listed as follow:1.1 Curcumin showed inhibition on CYP2D6, CYP3A4 and CYP2C9, and their IC50 value were 91.2,45.18 and 11.29μM, respectively.1.2 Puerarin showed inhibition on CYP3A4 and CYP1A2, and their IC50 values were 33.21 and 138.56μM, respectively.2. The studies of curcumin or puerarin with other drugs in vivo include:the effect of curcumin or puerarin on the pharmacokinetics of itself; the effect of curcumin or puerarin on the pharmacokinetics and pharmacodynamics of warfarin; the effect of curcumin or puerarin on the pharmacokinetics and pharmacodynamics of clopidogrel; the effect of curcumin on the pharmacokinetics of losartan; the effect of puerarin on the pharmacokinetics of theophylline. LC-MS/MS methods were developed for rapid determination of curcumin, puerarin, warfarin, clopidogrel, losartan and theophylline. In pharmacokinetics studies rats were divided into 4 groups for each experiment. Rats in three treatment groups were orally treated with curcumin or intraperitoneally treated with puerarin at three doses, respectively, for seven consecutive days. On the 7th day, the rats were gavaged with a single dose of drug (listed above) and blood was withdrawn at regular time. The samples were analysis and pharmacokinetics parameters were obtained. The AUC, T1/2, Cmax and CL of each drug were compared between control group and treatment groups. In pharmacodynamics studies, curcumin or puerarin were pre-administrated with other drugs, and the efficacy indexes were compared between control group and treatment groups.2.1 There were no marked changes in pharmacokinetic parameter of single or repeat administration of curcumin (100mg/kg) or puerarin (10mg/kg) in rats. 2.2 The pharmacokinetic profile of losartan affected by curcumin was revealed in rats. Compared with the control group, rats prior exposure to curcumin (100mg/kg) had significantly increased in AUC0-t and Cmax of losartan and its active metabolite EXP3174.2.3 Compared with rats gavaged with warfarin alone the main pharmacokinetic data were changed in those pretreated with curcumin 100mg/kg. AUC0-t and Cmax of warfarin in warfarin pretreated with curcumin (100mg/kg) group were significantly higher than those in control group, and the CL was lower in treatment group. PT and INR of rats have no significant difference when warfarin combination with curcumin.2.4 Compared with rats gavaged with clopidogrel alone the main pharmacokinetic data were changed in those pretreated with curcumin 100mg/kg. AUC0-t and Cmax of clopidogrel carboxylic acid in clopidogrel pretreated curcumin (100mg/kg) group was significantly higher than those in control group, and the CL was lower in treatment group. MAPR of rats have no significant difference when clopidogrel combination with curcumin.2.5 Compared with rats i.v. theophylline alone the main pharmacokinetic data were changing in those per-treatment with puerarin 200mg/kg. AUC0-t was lower and T1/2 was shorter than the control group.2.6 From the pharmacokinetic data of warfarin that higher warfarin concentrations in plasma for rats pretreated with puerarin than those gavaged with warfarin alone at all time points were observed. The AUC0-t and Cmax of warfarin in warfarin pretreated with puerarin (20 or 60 or 200mg/kg) groups were significantly higher than those in warfarin control group, and the CL were lower in treatment group. PT and INR of rats have no significant difference when warfarin combination with puerarin, and the same to any two of three groups with puerarin.2.7 The pharmacokinetic parameters of clopidogrel carboxylic acid after an oral dose of 30 mg/kg clopidogrel to rats, pre-treatment with or without puerarin (20mg/kg, 60mg/kg and 200mg/kg) are no statistically significant difference in clopidogrel carboxylic for rats pretreated with puerarin 20mg/kg,60mg/kg and 200mg/kg compared with those gavaged clopidogrel alone. Compared with clopidogrel alone group, the MAPR of clopidogrel pretreated with puerarin (20 or 60 or 200mg/kg) groups are significantly decreasing. Therefore, puerarin can enhance the antiplatelet activity of clopidogrel.