Effects of broad-spectrum antibiotics on the metabolism and pharmacokinetics of ginsenoside Rb1: A study on rats׳ gut microflora influenced by lincomycin

Abstract

Ginsenoside Rb1 is a biologically active compound that is abundant in ginseng (Panax ginseng). It has been reported that ginsenosides could be metabolized by enzymes and bacteria in the large intestine. In this study, the effects of intestinal bacteria on the metabolism and pharmacokinetics of ginsenoside Rb1 were investigated using lincomycin-treated rat models (4.8 g/kg and 0.12 g/kg). Specifically, ginsenoside Rb1 was incubated anaerobically with rat fecal suspensions obtained from the control and two model groups at 0, 6, 12, 24, and 48 h. Ginsenoside Rb1 and its metabolites were determined by HPLC analysis. Compared with the normal rats case where Rd and compound K were detected in the incubation mixture, ginsenoside Rd and F2 were found in the 0.12 g/kg group, but only Rd was found in the 4.8 g/kg group. Moreover, fecal β-glucosidase activity was significantly lower in lincomycin-treated (0.12 g/kg and 4.8 g/kg) model rats. After administration of Rb1 to rats, ginsenoside Rb1 and its metabolites Rd, Rg3, and Rh2 were detectable in normal rat urine, whereas none was detected in the two model groups. The plasma concentration-time Rb1 were compared between model groups and normal rats. The systemic exposure as evidenced by the AUC and T_1/2 values was significantly higher in model groups than in normal rats. Our findings demonstrated that consumption of lincomycin could lead to the formation of specific metabolites and pharmacokinetic changes of ginsenoside Rb1 in the gut, attributed to alterations in metabolic activities of intestinal bacteria. Our results also suggested that patients who want to use intestinal bacteria-metabolized drugs such as ginseng (Panax ginseng) should pay attention to the profile of intestinal bacteria or potential drug interactions to ensure therapeutic efficacy.

Introduction

Ginseng, the root of Panax ginseng C. A. Meyer (Araliaceae), has been used as a tonic or drug to treat various conditions such as debility, aging, stress, diabetes, insomnia, and sexual inadequacy for thousands of years in China, Korea, and Japan. Its active components are believed to be ginsenosides, which have been shown to be involved in modulating multiple physiological activities and are widely used for the pharmacological examination of the effects of ginseng (Leung and Wong, 2010). Ginsenosides are triterpene saponins, and most of them are composed of a dammarane skeleton (17 carbons in a four-ring structure) with various sugar moieties (e.g., glucose, rhamnose, xylose and arabinose) attached to the C-3 and C-20 positions (De Smet, 2002). Rb1 is the most abundant (0.22–0.62%) of all ginsenosides (Takino, 1994) and has various bioactivities, including neuroprotective effects on high glucose-induced neurotoxicity in hippocampal neurons (Liu et al., 2013), prevention of interleukin-1 beta-induced inflammation and apoptosis in human articular chondrocytes (Cheng et al., 2013), and preventive effects for neural injury during cerebral infarction (Jiang et al., 2013). Many studies have shown that ginsenosides, particularly ginsenoside Rb1, must be metabolized by human intestinal microbes after being taken orally (Tawab et al., 2003), and this metabolism might be dependent on the composition of gut microbiota (Kim et al., 2013a). Therefore, alterations in intestinal microflora may affect the metabolism and absorption of Rb1, and subsequently lead to changes in the biological activity exerted by Rb1. Nevertheless, these hypotheses need to be examined.

It is generally believed that broad-spectrum antibiotics can affect drug metabolism and uptake by changing the profile of intestinal bacteria and may cause adverse effects (Sung and Lee, 2008). Accordingly, antibiotics have also been used to induce germ-free characteristics in animals for investigating the metabolism of compounds of interest (Gustafsson and Norin, 1977, Canzi et al., 1985, Jin et al., 2010). Lincomycin, a member of the lincosamide group of antibiotics, has gained clinical acceptance as a major antibiotic for the treatment of diseases caused by gram-positive bacteria and anaerobic bacteria (Peschke et al., 1995, Giguère et al., 2006). Lincomycin has been used for the last four decades. Few studies are available to verify the effect of the administration of antibiotics on the metabolism of ginsenosides. In the present study, a pseudo-germ-free rat model treated with lincolnensis was used to investigate the metabolism and pharmacokinetics of ginsenoside Rb1 and was compared with the normal and clinical dose antibiotic-exposed animals.