Effects of Adamantyl Derivatives on Pharmacokinetic Behavior of Paclitaxel in Rats
- 주제(키워드) Paclitaxel , Adamantyl derivatives , Verapamil , P-glycoprotein , Oral bioavailability
- 등재 SCIE, SCOPUS, KCI등재
- 발행기관 KOREAN SOC APPLIED PHARMACOLOGY
- 발행년도 2017
- URI http://www.dcollection.net/handler/ewha/000000147242
- 본문언어 영어
- Published As http://dx.doi.org/10.4062/biomolther.2016.191
초록/요약
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.
more