Effects of Piperazine Derivative on Paclitaxel Pharmacokinetics
1
College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Korea
2
College of Pharmacy and Division of Life and Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Korea
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Pharmaceutics 2019, 11(1), 23; https://doi.org/10.3390/pharmaceutics11010023
Received: 16 November 2018
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Revised: 12 December 2018
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Accepted: 2 January 2019
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Published: 8 January 2019
Paclitaxel (PTX) is an anticancer agent that is used to treat many cancers but it has a very low oral bioavailability due, at least in part, to the drug efflux transporter, P-glycoprotein (P-gp). Therefore, this study was performed to enhance oral bioavailability of PTX. In this study, we investigated the effects of several piperazine derivatives on P-gp function in vitro. Compound 4 was selected as the most potent P-gp inhibitor from the in vitro results for examining the pharmacokinetic (PK) changes of PTX in rats. Compound 4 increased the AUCinf of PTX without alterations in the Cmax value. The elimination half-life was extended and the oral clearance decreased. Additionally, the Tmax was delayed or widened in the treatment groups. Therefore, the bioavailability (BA) of PTX was improved 2.1-fold following the co-administration of 5 mg/kg of the derivative. A piperazine derivative, compound 4, which was confirmed as a substantial P-gp inhibitor in vitro increased the BA of PTX up to 2-fold by a lingering absorption, in part due to inhibition of intestinal P-gp and a low oral clearance of PTX. These results suggest that co-administering compound 4 may change the PK profile of PTX by inhibiting P-gp activity in the body.
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Keywords:
piperazine derivatives; P-glycoprotein inhibitor; pharmacokinetics; bioavailability; paclitaxel
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MDPI and ACS Style
Lee, J.; Chae, S.W.; Oh, A.R.; Yoo, J.H.; Park Choo, H.-Y.; Rhie, S.J.; Lee, H.J. Effects of Piperazine Derivative on Paclitaxel Pharmacokinetics. Pharmaceutics 2019, 11, 23. https://doi.org/10.3390/pharmaceutics11010023
AMA Style
Lee J, Chae SW, Oh AR, Yoo JH, Park Choo H-Y, Rhie SJ, Lee HJ. Effects of Piperazine Derivative on Paclitaxel Pharmacokinetics. Pharmaceutics. 2019; 11(1):23. https://doi.org/10.3390/pharmaceutics11010023
Chicago/Turabian StyleLee, Jaeok, Song W. Chae, A R. Oh, Ji H. Yoo, Hea-Young Park Choo, Sandy J. Rhie, and Hwa J. Lee. 2019. "Effects of Piperazine Derivative on Paclitaxel Pharmacokinetics" Pharmaceutics 11, no. 1: 23. https://doi.org/10.3390/pharmaceutics11010023
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