Biomol Ther (Seoul)  
Effects of Adamantyl Derivatives on Pharmacokinetic Behavior of Paclitaxel in Rats
Kyung Mi Kim1,†, Kyeong Lee2,†, Kyusic Jang2, Yae Seul Moon1, Hwa Jeong Lee1,* and Sandy Jeong Rhie3,*
1Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, 2College of Pharmacy, Dongguk University, Goyang 10326, 3College of Pharmacy and Division of Life and Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea
E-mail: hwalee@ewha.ac.kr (Lee HJ), sandy.rhie@ewha.ac.kr (Rhie SJ)
Tel: +82-2-3277-3409 (Lee HJ), +82-2-3277-3023 (Rhie SJ)
Fax: +82-2-3277-2851 (Lee HJ), +82-2-3277-2851 (Rhie SJ)
The first two authors contributed equally to this work.
Received: August 23, 2016; Revised: October 28, 2016; Accepted: November 15, 2016; Published online: February 6, 2017.
© The Korean Society of Applied Pharmacology. All rights reserved.

Abstract
Paclitaxel (PTX) is one of the most frequently used anticancer agent for treating refractory ovarian cancer, metastatic breast cancer and non-small cell lung cancer. However, its oral administration is impeded by very low bioavailability (<5%) due to the Pglycopprotein (P-gp) efflux pump effect. This study investigated in vitro and in vivo P-gp inhibitory effects of adamantyl derivatives AC-603 and AC-786 in rats. Two adamantyl derivatives tested in this study increased the cytotoxicity of daunomycin (DNM) in P-gp overexpressed cell line by inhibiting P-gp efflux function. Pharmacokinetics of PTX with orally co-administered P-gp inhibitors were assessed in rats to improve PTX absorption. The pharmacokinetic parameters of PTX were determined in rats after intravenous (2 mg/kg) or oral (25 mg/kg) administration in the presence or absence of verapamil (a positive control), AC-603 or AC-786 (0.5 mg/kg or 5 mg/kg). Compared to control group (PTX alone), experimental groups (PTX with AC-603 or AC-786) significantly increased the area under the plasma concentration-time curve of PTX following oral administration by 1.7-2.2 fold. The volume of distribution and total clearance of PTX were decreased, while other parameters were not significantly changed. In conclusion, co-administration of AC-603 or AC-786 enhanced the relative bioavailability of orally administered PTX as compared to control.
Keywords: Paclitaxel, Adamantyl derivatives, Verapamil, P-glycoprotein, Oral bioavailability


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