Inhibition of P-Glycoprotein Leads to Improved Oral Bioavailability of Compound K, an Anticancer Metabolite of Red Ginseng Extract Produced by Gut Microflora

Abstract

ABSTRACT:Ginsenosides are hydrolyzed extensively by gut microflora after oral administration, and their metabolites are pharmacologically active against lung cancer cells. In this study, we measured the metabolism of various ginsenosides by gut microflora and determined the mechanisms responsible for the observed pharmacokinetic behaviors of its active metabolite, Compound K (C-K). The results showed that biotransformation into C-K is the major metabolic pathway of ginsenosides after the oral administration of the red ginseng extract containing both protopanaxadiol and protopanaxatriol ginsenosides. Pharmacokinetic studies in normal mice showed that C-K exhibited low oral bioavailability. To define the mechanisms responsible for this low bioavailability, two P-glycoprotein (P-gp) inhibitors, verapamil and cyclosporine A, were used, and their presence substantially decreased C-K's efflux ratio in Caco-2 cells (from 26.6 to <3) and significantly increased intracellular concentrations (by as much as 40-fold). Similar results were obtained when transcellular transport of C-K was determined using multidrug resistance 1 (MDR1)-overexpressing Madin-Darby canine kidney II cells. In MDR1a/b(؊/؊) FVB mice, its plasma C max and AUC 0-24h were increased substantially by 4.0-and 11.7-fold, respectively. These increases appear to be due to slower elimination and faster absorption of C-K in MDR1a/b(؊/؊) mice. In conclusion, C-K is the major active metabolite of ginsenosides after microflora hydrolysis of primary ginsenosides in the red ginseng extract, and inhibition/deficiency of P-gp can lead to large enhancement of its absorption and bioavailability.

Effects of polyethylene glycols on intestinal efflux pump expression and activity in Caco-2 cells

“…For example, in a study, a P-gp blocker was able to increase paclitaxel concentration in blood (Kang et al, 2001). In addition, Compound K, the major component obtained from ginsenosides metabolism which is being used in treatment of lung cancer, showed reduced plasma C max and AUC 0-24h when P-gp was inhibited (Yang et al, 2012).…”

“…For example, in a study, a P-gp blocker was able to increase paclitaxel concentration in blood (Kang et al, 2001). In addition, Compound K, the major component obtained from ginsenosides metabolism which is being used in treatment of lung cancer, showed reduced plasma C max and AUC 0-24h when P-gp was inhibited (Yang et al, 2012).On the other hand, some studies refused the role of P-gp in drug efflux. For example, in an experiment performed by Dickens et al, hypothesis claiming that P-gp is overexpressed at the epileptic focus was rejected as antiepileptic drugs like carbamazepine and lamotrigine were proven not to be substrate for P-gp (Dickens et al, 2013).…”

Combined Contribution of Increased Intestinal Permeability and Inhibited Deglycosylation of Ginsenoside Rb1 in the Intestinal Tract to the Enhancement of Ginsenoside Rb1 Exposure in Diabetic Rats after Oral Administration

“…In previous studies, diabetes downregulated intestinal P-gp function and Rh2 and C-K were identified as the substrate of P-gp (Liu et al, 2009;Yang et al, 2011Yang et al, , 2012; however, these findings were controversial, implying that increased Rb1 absorption may be associated with downregulation of intestinal P-gp Transport of FD4 (1 mg/ml) and FLU (0.1 mg/mL) from the apical to basal (A→B) direction was measured to evaluate the permeability of the Caco-2 monolayer cultured with 10% rat serum. (D) Rb1 (10 mM) transport across the Caco-2 monolayer cultured with 10% rat serum from both the A→B and B→A direction.…”

Validation of IMP Dehydrogenase Inhibitors in a Mouse Model of Cryptosporidiosis

“…The experiment protocol and calculation were described in our previous reports (58). Briefly, an HBSS containing the compound(s) of interest was loaded onto the apical or basolateral (donor) side.…”

“…The uptake of tested compounds was determined according to our previous protocol (58). Briefly, after the transport study, the cell membranes were rinsed three times with ice-cold HBSS, pH 7.4.…”