Biomol Ther.  2017 Sep;25(5):553-558. 10.4062/biomolther.2016.191.

Effects of Adamantyl Derivatives on Pharmacokinetic Behavior of Paclitaxel in Rats

• Kim KM
• Lee K
• Jang K
• Moon YS
• Lee HJ
• Rhie SJ

• KMID: 2389388
• DOI: http://doi.org/10.4062/biomolther.2016.191

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.

Keyword

Paclitaxel; Adamantyl derivatives; Verapamil; P-glycoprotein; Oral bioavailability

MeSH Terms

Absorption
Administration, Oral
Animals
Biological Availability
Breast Neoplasms
Carcinoma, Non-Small-Cell Lung
Cell Line
Daunorubicin
In Vitro Techniques
Ovarian Neoplasms
P-Glycoprotein
Paclitaxel*
Pharmacokinetics
Plasma
Rats*
Verapamil
Daunorubicin
P-Glycoprotein
Paclitaxel
Verapamil