Effects of Borneol on Pharmacokinetics and Tissue Distribution of Notoginsenoside R1 and Ginsenosides Rg1 and Re in Panax notoginseng in Rabbits

Abstract

The purpose of this study is to investigate the effects of Borneol on the pharmacokinetics of notoginsenoside R1 (NGR1) and the ginsenosides Rg1 (GRg1) and Re (GRe) in Panax notoginseng. Reversed phase high-performance liquid chromatography coupled with electrospray ion trap mass spectrometry was employed to determine the concentrations of the three compounds in rabbit plasma. In comparison with rabbits administrated Panax notoginseng extract alone, animals simultaneously taking Panax notoginseng extract and Borneol exhibited significant differences in pharmacokinetic parameters of NGR1, GRg1, and GRe, such as increasing their bioavailability. Quantities of NGR1, GRg1, and GRe in rabbit tissues were also increased after combining administration of Borneol. In addition, the apparent permeability coefficients (P app) of NGR1, GRg1, and GRe were raised by Borneol significantly in Caco-2 cells. However, no significant changes were observed in the efflux ratio (Er) of NGR1, GRg1 and GRe. These data indicate that Borneol has the properties of enhancing the intestinal absorption, increasing the distribution, and inhibiting the metabolism of NGR1, GRg1, and GRe. The underlying mechanism might be attributed to the loosening of the intercellular tight junction.

Figure 1

HPLC-MS ion chromatograms of plasma samples. (a) blank plasma samples; (b) plasma standard solutions of 5.0 μg·mL⁻¹ NGR1, 3.0 μg·mL⁻¹ GRg1, and 8.0 μg·mL⁻¹ GRe; (c) plasma samples after administration of Panax notoginseng extract at a dose volume of 3.0 mL·kg⁻¹.

Figure 2

Plasma concentration-time curves of NGR1 (a), GRg1 (b), and GRe (c) after administration of Panax notoginseng and Panax notoginseng combined with Borneol extracts in rabbit, respectively. The dose volume was 3.0 mL·kg⁻¹  and the fitted curves were obtained by analyzing the plasma concentration-time data with the Program DAS 2.0. ◆ rabbits administered Panax notoginseng extract; ■ rabbits administered Panax notoginseng combined with Borneol.

Figure 3

Effect of Borneol on TEER values of the Caco-2 cell monolayers. The Caco-2 cell monolayers were pretreated 2 h with 500 μM of NGR1, GRg1, and GRe, or the three saponins plus 200 μM Borneol. At time point 0, the monolayers were washed with buffered DMEM (pH 7.4), and then incubated at 37°C for 4 h.