Pharmacokinetic Drug Interaction Studies Of Irinotecan And Its Active Metabolite SN-38 With P-gp Inhibitors

In order to assess experimentally the intestinal permeability of the anticancer prodrug irinotecan, and to quantify the amount of its cytotoxic metabolite SN-38 that is intestinally excreted (exsorbed) as a predictor of intestinal toxicity, and to assess the effect of p-glycoprotein (P-gp) inhibitors (verapamil, pharmaceutical exipients, and grapefruit) on the permeability and toxicity of irinotecan, the improved form of the single pass intestinal perfusion (SPIP) model was used.And further in vivo experiments are done to further assess the pharmacokinetic interaction of P-gp inhibitors with irinotecan and its active metabolite SN-38 after oral administration of irinotecan.To achieve these goals, reversed phase isocratic high performance liquid chromatographic (HPLC) assay with UV detection is developed for quantification of irinotecan and SN-38 from perfusion samples, and from in vivo plasma samples.The HPLC-UV analytical method for the determination of the prodrug irinotecan and its active metabolite SN-38 was validated and found to be simple, specific, accurate, and precise. And used to apply the improved rat's in situ single pass intestinal perfusion (SPIP) technique to assess the permeability, and intestinal toxicity of irinotecan predicted to result from exsorbed SN-38.The effects of P-gp inhibitor verapamil were also successfully evaluated and found to increase the intestinal permeability and potentially decrease the intestinal toxicity encountered upon the administration of irinotecan.The effects of commonly used exipients (Cremophor El, Tween 80) was also evaluated and proved ability to increase the permeability while little or no effect on the amount of SN-38 exsorption. The effect of PEG 400 was also investigated to assess its potential effect on the intestinal permeability of irinotecan and the exsorption of SN-38 but neither of the two parameters found to be changed.The effect of grapefruit was also investigated and found to increase the intestinal permeability and potentially decrease the intestinal toxicity encountered upon the administration of irinotecan (due to SN-38 gut exposure).This method provided a useful tool for predicting oral absorption of irinotecan and the accompanying exsorbed SN-38 in the same experiment, in a manner that robustly reflects real in vivo situation.In addition the HPLC method was further validated for simultaneous assay of irinotecan and SN-38 from plasma samples, and found to be simple, specific, accurate, and precise, and was successfully applied to study the in vivo pharmacokinetics of irinotecan and SN-38 in rats, and to assess the effects of the P-gp modulators Cremophor El, Tween 80, and grapefruit, on the pharmacokinetic parameters of irinotecan and SN-38 compared to control.Introduction1.1. BackgroundIrinotecan 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin, also known as CPT-11, is a semisynthetic analog of the naturally occurring alkaloid, camptothecin (CPT). Irinotecan has been widely used for the treatment of colorectal cancer as both first-and second line-therapy (Potmesil,1994). Irinotecan has also shown clinical activity against colorectal, lung, gastric, cervical and ovarian cancers, malignant lymphoma and other malignancies (Ohno et al.,1990; Fukuoka et al.,1992;...