INFLUENCE OF P-GLYCOPROTEIN AND CYTOCHROME ISOENZYME-P3A4 ON BIOAVAILABILITY OF ANTICANCER DRUGS WITH CURCUMIN BY IN SITU INTESTINAL PERFUSION IN MALE WISTAR RATS

Objectives: An orally administered anticancer drug has been poor drug absorption; drug resistance and metabolism, which alters the bioavailability of drugs. An in situ intestine perfusion technique is developing under the different perfusion rates in the presence of drug inducers and inhibitors of cytochrome isoenzyme-P (CYP)-3A4 and P-glycoprotein (P-gp) for drug concentrations. Materials and Methods: The modified in situ intestinal perfusion technique was developed and followed to obtain the portal and hepatic venous blood samples paralleled at different perfusion time and flow rates of 0.05, 0.1, 0.5, and 1.0 mL/min using the imatinib (1 mg/mL) drug alone and in the presence of drug inducer and drug inhibitor for the period of 3 h. The imatinib drug concentrations were assayed using high-pressure liquid chromatography. Results: The results reveal that the mean imatinib drug concentrations in portal vein were higher than hepatic vein at various perfusion flow rates and time intervals were observed. The area under curve and plasma drug concentrations maximum of imatinib alone absorptions were significantly different between portal and hepatic veins (p<0.05) at the flow rates of 0.5 and 1.0 mL/min and also in the presence of drug inducer and inhibitors that indicating for the considerable hepatic involvement in the presystemic extraction or metabolism of drugs. Conclusions: The in situ perfusions approach could provide the useful tool for improving the basic understanding of absorption kinetics and hepatic metabolism of drugs in the presence of drug inducers and drug inhibitors (CYP3A4 and P-gp) under the development and facilitating the clinical applications.

In Situ Intestinal Perfusion of Irinotecan: Application to P-gp Mediated Drug Interaction and Introduction of an Improved HPLC Assay

PURPOSE: To determine experimentally the intestinal permeability of the anticancer prodrug irinotecan, and to quantify the amount of its cytotoxic metabolite SN-38 that is intestinally excreted (exsorped) as a predictor of intestinal toxicity, and to assess the effect of p-glycoprotein (p-gp) inhibitors (verapamil as a model) on the permeability and toxicity of irinotecan. METHODS: Single pass intestinal perfusion of rat’s whole length small intestines is applied to assess the permeability of the parent drug and quantify the intestinally excreted metabolite. The perfusion solution contained 30μg/ml of irinotecan (control group) without or with verapamil (verapamil group). A simple reversed phase HPLC method with UV detection is developed and validated for simultaneous determination of irinotecan and SN-38 using camptothecin as an internal standard. RESULTS: HPLC-UV method found to be simple, specific, accurate, and precise. Effective permeability coefficient of irinotecan found to be 4.9±1.7 10-3 mm/min and was doubled in verapamil group (P=0.007). Average cumulative amount of SN-38 exsorped found to be 29 ng/cm over 2 hours perfusion time which was decreased to 15 ng/cm in verapamil group (P=0.016). CONCLUSIONS: in situ intestinal perfusion method was successfully applied to quantify the permeability of irinotecan and the exsorption of SN-38 in the same experiment, in a manner that robustly reflects real in vivo situation. P-gp inhibition using verapamil found to significantly enhance the intestinal permeability of irinotecan and potentially decrease the intestinal toxicity due to SN-38 exposure. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.