From biopharmaceutical studies of Pueraria lobata to herb - drug interactions

• Main Authors: Hsiu-Mei Chiang, 江秀梅
• Other Authors: Pei-Dawn Lee
• Format: Others
• Language: zh-TW
• Published: 2005
• Online Access: http://ndltd.ncl.edu.tw/handle/12663185352616140107

博士 === 中國醫藥大學 === 藥物化學研究所 === 93 === Pueraria Radix (PR), the roots of Pueraria lobata OWHI is an isoflavone-rich Chinese herb and also a food in oriental countries. Puerarin, daidzin and daidzein are bioactive isoflavone constituents of PR. The aims of this study were (1) to investigate the metabolic pharmacokinetics of isoflavones after oral administrations of commercial and ethanol extract of PR in rats, (2) to measure the effects of PR decoction on the pharmacokinetics of methotrexate (MTX) and valproic acid (VPA), and (3) to measure the effect of PR in extracellular acetylcholine release on rat hippocampus. Rats were given commercial and ethanol extract of PR and blood samples were withdrawn via cardiopuncture and assayed by HPLC method after enzymatic hydrolysis with β-glucuronidase and sulfatase, respectively. Daidzein sulfates were found predominantly in the bloodstream, whereas daidzein glucuronides presented in less amount. Microdialysis technique was used for pharmacodynamic study of PR, the effect of PR after oral dosing on the extracellular acetylcholine release in rat hippocampus was not significant. MTX and VPA are two western medicines with narrow therapeutic index, and thus were used as model drugs to explore the herb - drug interaction which is an important public health issue in Taiwan. MTX and VPA are carboxylic acids and being substrates of multidrug resistance proteins (MRPs) and organic anion transporters (OATs). The isoflavones of PR were metabolized into sulfates and glucuronides in the body, both metabolites are also reported as substrates of MRPs and OATs. These metabolites may compete the transporters with MTX and VPA. This study investigated the effects of PR decoction on the pharmacokinetics of MTX and VPA in rats. The blood concentrations of MTX and VPA were determined by monoclonal fluorescence polarization immunoassay (FPIA) method. The systemic exposure of MTX and VPA were significantly increased after oral coadministration of PR decoction. In addition, when MTX and VPA were given intravenously, the coadministration of PR decoction significantly decreased the clearance of MTX and VPA. Therefore, the enhanced of exposure of MTX and VPA by coadministration of PR can be ascribed to the decreased elimination of MTX and VPA. In order to ensure safety, concurrent intake of MTX or VPA with PR should be discouraged. Cyclosporin (CsA) is a widely used immunosuppressant with narrow therapeutic range. CsA was used as a model drug, representing CYP3A4/P-gp substrates, to investigate interactions with herbs including ginseng, American ginseng, notoginseng, cordyceps and ginger juice. Our results showed that all the herbs except notoginseng significantly decreased the bioavalibility of CsA. However, the pharmacokineties of intravenous CsA were not altered. This suggested that the interactions occurred at the absorption site. For the sake of efficacy, the coadiministraction of these herbs with CsA should be avoided. In summary, using pharmacokinetic approach can better understand the biological fate of herbal contents, and furthermore, the hidden risk of herb - drug interactions can be explored.