| Metabolism and pharmacokinetics of the active compounds of botanical dietary supplements (BDS) are essential to their safety and efficacy. In this dissertation, several assays were combined with high performance liquid chromatography-mass spectrometry (HPLC-MS) for the metabolism and pharmacokinetic studies of the active compounds in three dietary supplements: Trifolium pratense (red clover), Cimicifuga racemosa (black cohosh), and Piper methysticum (kava).; LC-MS was used for the quantitation of daidzein, genistein, biochanin A, and formononetin in human serum and urine collected during a Phase I clinical trial. The results indicated that the abundant but weakly estrogenic isoflavones in red clover, biochanin A and formononetin, were rapidly O-demethylated in the liver and possibly in the gut to form the much more estrogenic metabolites genistein and daidzein.; The inhibition of human liver CYP450 isozymes by the standardized red clover extract was investigated for possible herbal-drug interactions. The red clover extract inhibits CYP2C9 with an IC50 of 1.0mug/mL and 3A4 with an IC50 value of 16.6 mug/mL.; In another assay using ultrafiltration LC-MS-MS, eleven GSH adducts of monohydroxylated isoflavones were detected. LC-MSn was used to characterize the structures of the conjugates and the regioisomers were differentiated. However, no mercapturic acids were detected in the urine samples collected during the Phase I clinical trial.; A LC-MS-MS method was developed for the quantitation of 23-epi-26-deoxyactein in human serum and urine collected during a Phase I clinical trial. Following oral dose, 23-epi-26-deoxyactein was quickly eliminated with a half-life about 2 h. During the first 24 h, less than 0.01% of the administered 23-epi-26-deoxyactein was recovered in urine indicating that 23-epi-26-deoxyactein was either poorly absorbed or excreted by alternative routes such as in bile.; The mechanism of the kava related hepatotoxicity by forming electrophilic metabolites of methysticin and 7,8-dihydromethysticin was investigated. Both 7,8-dihydromethysticin and methysticin were O-demethylenated predominantly by the cytochrome P450 family CYP2C with CYP2C9 as the major contributor. |
