TY - JOUR T1 - Combinatorial Metabolism Notably Affects Human Systemic Exposure to Ginsenosides from Orally Administered Extract of <em>Panax notoginseng</em> Roots (Sanqi) JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1457 LP - 1469 DO - 10.1124/dmd.113.051391 VL - 41 IS - 7 AU - Hu, Zheyi AU - Yang, Junling AU - Cheng, Chen AU - Huang, Yuhong AU - Du, Feifei AU - Wang, Fengqing AU - Niu, Wei AU - Xu, Fang AU - Jiang, Rongrong AU - Gao, Xiumei AU - Li, Chuan Y1 - 2013/07/01 UR - http://dmd.aspetjournals.org/content/41/7/1457.abstract N2 - Ginsenosides are medicinal ingredients of the cardiovascular herb Panax notoginseng roots (Sanqi). Here, we implemented a human study (ChiCTR-ONC-09000603; www.chictr.org) to characterize pharmacokinetics and metabolism of ginsenosides from an orally ingested Sanqi-extract (a 1:10 water extract of Sanqi) and the human plasma and urine samples were analyzed by liquid chromatography-mass spectrometry. Plasma and urinary compounds derived from ginsenosides included: 1) intestinally absorbed ginsenosides Ra3, Rb1, Rd, F2, Rg1, and notoginsenoside R1; and 2) the deglycosylated products compound-K, 20(S)-protopanaxadiol, 20(S)-protopanaxatriol, and their oxidized metabolites. The systemic exposure levels of the first group compounds increased as the Sanqi-extract dose increased, but those of the second group compounds were dose-independent. The oxidized metabolites of 20(S)-protopanaxadiol and 20(S)-protopanaxatriol represented the major circulating forms of ginsenosides in the bloodstream, despite their large interindividual differences in exposure level. The metabolites were formed via combinatorial metabolism that consisted of a rate-limiting step of ginsenoside deglycosylation by the colonic microflora and a subsequent step of sapogenin oxidation by the enterohepatic cytochrome P450 enzymes. Significant accumulation of plasma ginsenosides and metabolites occurred in the human subjects receiving 3-week subchronic treatment with the Sanqi-extract. Plasma 20(S)-protopanaxadiol and 20(S)-protopanaxatriol could be used as pharmacokinetic markers to reflect the subjects’ microbial activities, as well as the timely-changes and interindividual differences in plasma levels of their respective oxidized metabolites. The information gained from the current study is relevant to pharmacology and therapeutics of Sanqi. ER -