Combinatorial Metabolism Notably Affects Human Systemic Exposure to Ginsenosides from Orally Administered Extract of Panax notoginseng Roots (Sanqi)

Abstract

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 chromatographymass spectrometry. Plasma and urinary compounds derived from ginsenosides included: 1) intestinally absorbed ginsenosides Ra 3 , Rb 1 , Rd, F 2 , Rg 1 , and notoginsenoside R 1 ; 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 doseindependent. 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 timelychanges 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.

Renal Tubular Secretion of Tanshinol: Molecular Mechanisms, Impact on Its Systemic Exposure, and Propensity for Dose-Related Nephrotoxicity and for Renal Herb-Drug Interactions

“…An herbal constituent can be defined as drug-like if it possesses the desired pharmacologic potency, a wide safety margin, appropriate pharmacokinetic (PK) properties, and adequate content in the medicine dosed. Recent multicompound PK studies have indicated that human subjects and laboratory animals are considerably exposed to only a few constituents of an herbal medicine after dosing (Lu et al, 2008;Liu et al, 2009;Li et al, 2012a;Chen et al, 2013;Cheng et al, 2013;Hu et al, 2013;Jiang et al, 2015;Li et al, 2015). Such PK studies provide information for pharmacologists regarding which herbal compounds merit further evaluation.…”

Systemic Exposure to and Disposition of Catechols Derived from Salvia miltiorrhiza Roots (Danshen) after Intravenous Dosing DanHong Injection in Human Subjects, Rats, and Dogs

“…(2)-Epicatechin was used as the positive control to assess the catechol-O-methyltransferase (COMT) activities of the human, rat, and dog liver cytosols (Zhu et al, 2000;Li et al, 2012), and the in vitro t 1/2 values were 0.46, 0.08, and 0.21 hour, respectively. 7-Hydroxyflavone was used as the positive control to assess the sulfotransferase (SULT) activities of the human, rat, and dog liver cytosols (Li et al, 2012;Hu et al, 2013), and the in vitro t 1/2 values were 0.07, 0.29, and 0.10 hour, respectively. Chrysin was used as the positive control to assess the UDP-glycosyltransferase (UGT) activities of the human, rat, and dog liver microsomes (Li et al, 2012;Hu et al, 2013), and the in vitro t 1/2 values were 0.08, 0.05, 0.05 hour, respectively.…”

Pharmacokinetics and disposition of monoterpene glycosides derived from Paeonia lactiflora roots (Chishao) after intravenous dosing of antiseptic XueBiJing injection in human subjects and rats

“…It is hypothesized that the active principles responsible for the therapeutic effects of an herbal medicine come from a few constituents with favorable drug-like properties, including the desired pharmacologic potency, a wide safety margin, appropriate pharmacokinetic (PK) properties, and adequate content in the dosed medicine [9,10] . Recent multicompound PK studies of herbal medicines indicate notable differences between the circulating herbal compounds and the chemical ingredients of the dosed medicine [9,[11][12][13][14][15][16][17] . Pharmacologically active herbal compounds that exhibit considerable levels of body exposure after dosing an herbal medicine are the most likely to form the basis of therapeutic efficacy of the medicine.…”