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Molecules 2018, 23(2), 349; https://doi.org/10.3390/molecules23020349

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

1
College of Pharmacy, Catholic University of Daegu, Gyeongsan 38430, Gyeongbuk, Korea
2
College of Pharmacy, Wonkwang University, Iksan 54538, Jeonbuk, Korea
3
School of Pharmacy, Sungkyunkwan University, Suwon 16419, Gyeonggi-do, Korea
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Received: 3 January 2018 / Revised: 26 January 2018 / Accepted: 31 January 2018 / Published: 7 February 2018
(This article belongs to the Section Natural Products Chemistry)
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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, Kp, for the liver and kidney were higher in the piperine-pretreated group, while the Kp 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. View Full-Text
Keywords: P-glycoprotein; doxorubicin; pharmacokinetics; piperine; capsaicin; [6]-gingerol P-glycoprotein; doxorubicin; pharmacokinetics; piperine; capsaicin; [6]-gingerol
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Kim, T.H.; Shin, S.; Yoo, S.D.; Shin, B.S. Effects of Phytochemical P-Glycoprotein Modulators on the Pharmacokinetics and Tissue Distribution of Doxorubicin in Mice. Molecules 2018, 23, 349.

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