ABSTRACT
OBJECTIVE: To develop a high performance liquid chromatography method for the determination of imatinib in rat plasma and study its pharmacokinetics. METHODS: Plasma was deposited by perchloric acid. The analytical column was ZORBAX SB-C18 (4.6 mm × 150 mm, 5 μm). The mobile phase was acetonitrile-water-0.1% trifluoroacetic acid (19:61:20) and the flow rate was 1.0 mL · min-1. The LV detection wavelength was 282 nm. Six male SD rats were given a single dose of 50 mg · kg-1 imatinib by garage. Blood samples were collected from tail vein at different time points. The concentrations of imatinib in plasma were determined by the established HPLC method. The pharmacokinetic parameters were analyzed by DAS program. RESULTS: Excellent liner relationship was obtained in the range of 0.10-20.00 mg · L-1 (r=0.9998), and the lower limit of qauntification was 0.05 mg ·L-1. The recoveries were (98.86±2.77)%, (100.35±2.31)% and (100.14±1.66)% respectively at three concentrations (0.25, 5.00, 15.00 mg · L-1), the intra-day RSDs were 2.64%, 2.50% and 1.62% with REs of -1.60%, -1.00% and 0.10%, and the inter-day RSDs were 3.51%, 2.77% and 1.34% with REs of -0.80%, 0.72% and 0.21%, respectively. After oral administration in rats, the pharmacokinetic profile of imatinib was fitted with a two-compartment model, the half-lives of α phase and β phase were (2.40±0.84) h and (7.82±0.87) h, respectively. CONCLUSION: The method is accurate, simple, rapid and can be used to determine imatinib concentration in rat plasma and study its pharmacokinetics.
ABSTRACT
Exogenous wild-type p53 (wt-p53) tumor suppression increases the sensitivity of tumor cells to radiotherapy and chemotherapy. An iodized oil emulsion was used as a p53 vector for intra-arterial gene delivery to treat hepatic tumors. Whether the chemotherapeutic agent or the iodized oil affects exogenous wt-p53 activity remains poorly understood. In the present study, the early therapeutic response of rAd/p53, combined with 5-fluorouracil (5-FU) or with iodized oil, was observed in a human colon cancer model. Allograft models in 82 nude mice with human colon carcinoma SW480 were divided randomly into four groups and administered with physiologic saline, rAd/p53, rAd/p53+5-FU, and rAd/p53+iodized oil by intratumoral injection. At 24, 48, 72, 120, and 168 h after treatment, p53 expression, the Ki-67 index (KI), and the degree of tumor necrosis were assessed. The p53 expression and tumor necrosis in the therapeutic groups were higher than those in the control group. p53 expression reached its peak at 120 h in the rAd/p53 group, at 72 h in the rAd/p53+5-FU group, and at 48 h in the rAd/p53+iodized oil group. The p53 expression in the rAd/P53+5-FU group and the iodized oil group was significantly higher than those in the rAd/P53 group at 24 and 48 h. The results revealed that tumor necrosis is positively correlated with p53 expression. The KI of the rAd/p53+5-FU group increased significantly at 24 h. 5-FU and iodized oil increase the anticancer effect of rAd/p53, and 5-FU combined with rAd/p53 has a synergistic anticancer effect.
