| Summary: | 碩士 === 長庚大學 === 天然藥物研究所 === 91 === Anti-cancer drugs currently used are classified as cytotoxic agents. These drugs not only caused side effects but also showed low efficacy. TW01, a compound synthesized in our laboratory showed profound in vitro anticancer activities against a variety of human tumor cell lines. This compound also showed significant anti-angiogenesis effect in mice. As optimized formulation of drug pharmacokinetic (PK) profile can improve drug pharmacodynamic activity, this study aims to establish the analytical method to investigate the PK profile of TW01.
In this study, assay method for analyzing TW01 in biological fluid was first established by HPLC. Under this method, the recovery rate was 96.36 ± 7.31 %. The limit of detection (LOD) and the limit of quantitation (LOQ) were 3.90 ng/mL and 7.81 ng/mL, respectively. Validation was made by the evaluation of the intra-day and inter-day precision and accuracy. The coefficient of variation was 15 % and the relative error was 20 %.
TW01 was then administered orally (30 mg/Kg) or injected intravenously (0.7 mg/Kg) into the tail vein of Wistar rats. Plasma concentration-time profile of TW01 was established. The pharmacokinetic parameters were determined by calculation with WinNonlin program based on the noncompartment model from the plasma concentration-time data. After i.v. injection of TW01 (0.48 mg/mL, a solution of 3.6 mg TW01 in 7.5 mL of Cremophor EL : ethanol = 1 : 1 solvent), the AUC was 1.31 ± 0.56 hr.μg/mL . The maximum blood concentration (Cmax) was 1.58 ± 0.67 μg/mL. The clearance was 768.62 ± 373.91 mL/hr/Kg and the volume of distribution was 1384.54 ± 709.60 mL/Kg. The half-life was 2.34 ± 1.31 hours and the mean residue of time (MRT) was 1.78 ± 0.40 hours. The AUC after oral administration of TW01 (a suspension of 57.8 mg TW01 in 36.0 mL of (Cremophor EL : ethanol = 1 : 1) : H2O = 19 : 1 solvent) was 0.52 ± 0.14 hr.μg/mL. The maximum blood concentration of TW01 (Cmax) was 0.18 ± 0.09 μg/mL and the time to reach maximal concentration (Tmax) was 1.06 ± 0.33 hours. The clearance was 677.86 ± 359.20 mL/hr/Kg and the volume of distribution was 1991.92 ± 927.07 mL/Kg. The half-life was 2.70 ± 1.54 hours and the mean residue of time was 3.16 ± 1.26 hours. Oral bioavailability of TW01 (30 mg/Kg) was calculated to be 1.14 ± 0.61 %.
The low oral bioavailability might be due to the low solubility of TW01 in Cremophor EL : ethanol = 1 : 1 vehicle. As low dose (10 mg/Kg) of TW01 showed promising antitumor activity in nude mice bearing HA22T hepatoma, it is necessary to seek for vehicles to improve the solubility of TW01 and optimize the pharmacokinetic profile.
|
|---|
