Effects of Phytochemical P-Glycoprotein Modulators on the Pharmacokinetics and Tissue Distribution of Doxorubicin in Mice

Abstract

Pungent spice constituents such as piperine, capsaicin and [6]-gingerol consumed via daily diet or traditional Chinese medicine, have been reported to possess various pharmacological activities. These dietary phytochemicals have also been reported to inhibit P-glycoprotein (P-gp) in vitro and act as an alternative to synthetic P-gp modulators. However, the in vivo effects on P-gp inhibition are currently unknown. This study aimed to test the hypothesis that phytochemical P-gp inhibitors, i.e., piperine, capsaicin and [6]-gingerol, modulate the in vivo tissue distribution of doxorubicin, a representative P-gp substrate. Mice were divided into four groups and each group was pretreated with intraperitoneal injections of control vehicle, piperine, capsaicin, or [6]-gingerol and doxorubicin (1 mg/kg) was administered via the penile vein. The concentrations of the phytochemicals and doxorubicin in the plasma and tissues were determined by LC-MS/MS. The overall plasma concentration-time profiles of doxorubicin were not significantly affected by piperine, capsaicin, or [6]-gingerol. In contrast, doxorubicin accumulation was observed in tissues pretreated with piperine or capsaicin. The tissue to plasma partition coefficients, K_p, for the liver and kidney were higher in the piperine-pretreated group, while the K_p for kidney, brain and liver were higher in the capsaicin-pretreated group. [6]-Gingerol did not affect doxorubicin tissue distribution. The data demonstrated that the phytochemicals modulated doxorubicin tissue distribution, which suggested their potential to induce food-drug interactions and act as a strategy for the delivery of P-gp substrate drugs to target tissues and tumors.

Keywords: P-glycoprotein; [6]-gingerol; capsaicin; doxorubicin; pharmacokinetics; piperine.

Figure 1

Plasma concentration vs. time profiles of piperine, capsaicin and [6]-gingerol after intraperitoneal injection in mice (n = 6, mean ± SD).

Figure 2

Tissue concentrations of piperine, capsaicin and [6]-gingerol after intraperitoneal administration in mice (n = 6, mean ± SD).

Figure 3

Plasma concentration vs. time profiles of doxorubicin after intravenous injection of doxorubicin at 1 mg/kg in mice pretreated with vehicle (control), piperine, capsaicin, or [6]-gingerol (n = 6, mean ± SD).

Figure 4

Tissue to plasma partition coefficients (K_p) of doxorubicin 2, 8 and 24 h after intravenous injection of doxorubicin at 1 mg/kg in mice pretreated with vehicle (control), piperine, capsaicin, or [6]-gingerol (n = 6, mean ± SD). * p < 0.05 vs. control.