Characterization of Pharmacokinetic Profiles and Metabolic Pathways of 20(S)-Ginsenoside Rh1in vivoandin vitro

Abstract

20(S)-Ginsenoside Rh1 is one of the important protopanaxatriol ginsenosides and has been reported to be the main hydrolysis product reaching the systemic circulation after oral ingestion of ginseng. However, its pharmacokinetic characteristics and metabolic fate have never been reported. The present study was therefore designed to elucidate its pharmacokinetic profiles and metabolic pathways both in vivo and in vitro. The absolute bioavailability of 20(S)-ginsenoside Rh1 in rats was only 1.01 %. Identification of metabolites showed that, after intragastrical administration of ginsenoside Rh1, two mono-oxygenated metabolites were detected from the urine, bile, liver tissue, and intestinal tract content, while the de-glucosylated product, 20(S)-protopanaxatriol, was only found in the contents of the intestinal tract. An in vitro incubation study confirmed that the CYP450-catalyzed mono-oxygenation, the intestinal bacteria mediated de-glucosylation, and the gastric acid mediated hydration reaction were the main metabolic pathways of 20(S)-ginsenoside Rh1. The presystemic metabolism as evidenced from this study may partially explain its poor bioavailability.

Microsomal Cytochrome P450-Mediated Metabolism of Protopanaxatriol Ginsenosides: Metabolite Profile, Reaction Phenotyping, and Structure-Metabolism Relationship

“…As seen from the fragment patterns of both parent compounds and metabolites, the oxygenation metabolism site on the C20 aliphatic branch chain was proposed. This result obtained from the in vitro hepatic microsome incubations was consistent with our previous study in vivo of Rh1 (Lai et al, 2009a) and also with previous reports in vivo of the typical PPD ginsenosides Rh2 (Qian et al, 2005a) and Rb1 (Qian et al, 2006). By a comparison with the authentic standards (RF11 and RT5), one of the oxygenation sites was confirmed on the C24 -25 double bond to produce C20 -24 epoxides (ocotillol-type ginsenosides) after rearrangement immediately from the C24 and C25 epoxides.…”

“…Although oral bioavailability and plasma levels of ginsenosides are generally low because of their extensive presystematic metabolism and poor membrane permeability (Tawab et al, 2003), previous studies from our laboratory and others showed that the hepatic levels of ginsenosides after oral ingestion were much higher than those in plasma and other tissues (Gu et al, 2009;Liu et al, 2009). In addition, oxygenated metabolites have actually been identified in bile and urine samples after oral ingestion of ginsenosides (Lai et al, 2009a;Liu et al, 2009). Such evidence suggests that hepatic cytochrome P450 may play an important role in the systematic disposition of ginsenosides.…”

“…To date, little is known about the further metabolic fate of such ginsenosides and their degradation products absorbed into the circulation system, where hepatic microsomal drug-metabolizing enzymes play an important role in disposition of many synthesized drugs and natural products. We have recently identified two monooxygenated metabolites from bile and urine samples of rats treated intravenously with ginsenoside Rh1 and also from in vitro hepatic microsomal incubation media (Lai et al, 2009a). Oxygenated metabolites had been also identified for Rg3 (Qian et al, 2005b), Rh2 (Qian et al, 2005a), and Rd in rats and for PPT in rat hepatic microsomes (Kasai et al, 2000).…”

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“…By using the ADMET (absorption, distribution, metabolism, excretion, and toxicity) model, G-Rh1 was predicted to have favorable aqueous solubility and oral absorption in the human gastrointestinal tract [82]. However, this contradicted the results of a previous study by Lai et al [85], which investigated the pharmacokinetic parameters and bioavailability of G-Rh1 using intravenous and intragastrical administrations in Sprague-Dawley rats. They found that this compound exhibited extremely poor absolute bioavailability of about 1 % and rapid clearance with a short elimination half-life as can be seen in other protopanaxatriol ginsenosides [86].…”

“…They found that this compound exhibited extremely poor absolute bioavailability of about 1 % and rapid clearance with a short elimination half-life as can be seen in other protopanaxatriol ginsenosides [86]. The phenomenon might be partly explained by its main metabolic pathways, including CYP450-catalyzed mono-oxygenation, the intestinal bacteria mediated deglucosylation, and the gastric acid mediated hydration reaction [85]. To overcome this problem, Yang et al [87] encapsulated G-Rh1 into self-microemulsions comprising P-pg and/or CYP450 inhibitory excipients.…”