Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Effects of Adamantyl Derivatives on Pharmacokinetic Behavior of Paclitaxel in Rats

  • Kim, Kyung Mi (Graduate School of Pharmaceutical Sciences, Ewha Womans University) ;
  • Lee, Kyeong (College of Pharmacy, Dongguk University) ;
  • Jang, Kyusic (College of Pharmacy, Dongguk University) ;
  • Moon, Yae Seul (Graduate School of Pharmaceutical Sciences, Ewha Womans University) ;
  • Lee, Hwa Jeong (Graduate School of Pharmaceutical Sciences, Ewha Womans University) ;
  • Rhie, Sandy Jeong (College of Pharmacy and Division of Life and Pharmaceutical Sciences, Ewha Womans University)
  • Received : 2016.08.23
  • Accepted : 2016.11.15
  • Published : 2017.09.01
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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 P-glycopprotein (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

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