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

Abstract

Aim: Monoterpene glycosides derived from Paeonia lactiflora roots (Chishao) are believed to be pharmacologically important for the antiseptic herbal injection XueBiJing. This study was designed to characterize the pharmacokinetics and disposition of monoterpene glycosides.

Methods: Systemic exposure to Chishao monoterpene glycosides was assessed in human subjects receiving an intravenous infusion and multiple infusions of XueBiJing injection, followed by assessment of the pharmacokinetics of the major circulating compounds. Supportive rat studies were also performed. Membrane permeability and plasma-protein binding were assessed in vitro.

Results: A total of 18 monoterpene glycosides were detected in XueBiJing injection (content levels, 0.001-2.47 mmol/L), and paeoniflorin accounted for 85.5% of the total dose of monoterpene glycosides detected. In human subjects, unchanged paeoniflorin exhibited considerable levels of systemic exposure with elimination half-lives of 1.2-1.3 h; no significant metabolite was detected. Oxypaeoniflorin and albiflorin exhibited low exposure levels, and the remaining minor monoterpene glycosides were negligible or undetected. Glomerular-filtration-based renal excretion was the major elimination pathway of paeoniflorin, which was poorly bound to plasma protein. In rats, the systemic exposure level of paeoniflorin increased proportionally as the dose was increased. Rat lung, heart, and liver exposure levels of paeoniflorin were lower than the plasma level, with the exception of the kidney level, which was 4.3-fold greater than the plasma level; brain penetration was limited by the poor membrane permeability.

Conclusion: Due to its significant systemic exposure and appropriate pharmacokinetic profile, as well as previously reported antiseptic properties, paeoniflorin is a promising XueBiJing constituent of therapeutic importance.

Figures

Figure 1

LC/TOF-MSE-based detection and measurement of Chishao monoterpene glycosides present in XueBiJing injection. (A) Chromatogram of XueBiJing injection showing the detection of Chishao monoterpene glycosides; (B) mean content levels of monoterpene glycosides in the raw materials of Chishao (P lactiflora roots); (C) mean content levels of monoterpene glycosides in different lots of XueBiJing injection (lot numbers: 1309271, 1309281, 1309291, 1309301, 1405301, 1406161, 1408191, and 1410081); (D) clinical daily doses of monoterpene glycosides from XueBiJing injection (1309301); (E) percentage doses of monoterpene glycosides in the total dose of monoterpene glycosides in XueBiJing injection (1309301). The chemical names and detection information of monoterpene glycosides (shown as compound ID) are listed in Table 1.

Figure 2

Systemic exposure to and excretion of Chishao monoterpene glycosides in human subjects (A–B) and rats (C–E) intravenously receiving XueBiJing injection. The chemical names of monoterpene glycosides (shown as compound ID) are listed in Table 1. The symbol “×” (in red) denotes the monoterpene glycoside that was not detected. The human subjects received a 75-min intravenous infusion of 100-mL XueBiJing injection (diluted in 100 mL of 0.9% NaCl injection). The rats received a 30-min intravenous infusion of the injection at 10 mL/kg. Because of the sample pooling, no standard deviation is shown.

Figure 3

Mean plasma concentrations of paeoniflorin (5) over time in male (solid circles) and female human subjects (open circles) receiving an intravenous infusion of XueBiJing injection (A). Red lines: the subjects receiving a 75-min intravenous infusion of 100-mL XueBiJing injection (diluted in 100 mL of 0.9% NaCl injection); blue lines: the subjects receiving a 150-min infusion of 100-mL XueBiJing injection (diluted in 200 mL of 0.9% NaCl injection); green lines: the subjects receiving a 75-min infusion of 50-mL XueBiJing injection (diluted in 100 mL of 0.9% NaCl injection). In addition, six of the male subjects continued to receive the same dose of the injection (green line) each day for the following six days; panel (B): mean plasma concentrations of 5 over time on d 7; panel (C): mean daily plasma concentrations of 5 at 0 (solid triangles) and 75 min (solid circles) after daily dosing from d 1 to d 7. Each milliliter of the injection contained 1.14 mg of 5.

Figure 4

Mean plasma concentrations of paeoniflorin (5) over time in rats receiving a 30-min intravenous infusion of XueBiJing injection at 5 (green line), 10 (blue line), and 20 mL/kg (red line) (A) and an intravenous bolus dose of XueBiJing injection at 10 mL/kg (blue solid line) and purified paeoniflorin at 11.4 mg/mL (blue dashed line) (B). Each milliliter of the injection contained 1.14 mg of 5.