Effects of Adamantyl Derivatives on Pharmacokinetic Behavior of Paclitaxel in Rats.
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 investigatedin vitroandin vivoP-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.
Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea.
Kyung Mi
KM
Kim
College of Pharmacy, Dongguk University, Goyang 10326, Republic of Korea.
Kyeong
K
Lee
College of Pharmacy, Dongguk University, Goyang 10326, Republic of Korea.
Kyusic
K
Jang
Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea.
Yae Seul
YS
Moon
Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea.
Hwa Jeong
HJ
Lee
College of Pharmacy and Division of Life and Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea.
Sandy Jeong
SJ
Rhie
Adamantyl derivatives; Oral bioavailability; P-glycoprotein; Paclitaxel; Verapamil