Investigations into the Mechanisms that Are Responsible for Reduction in Colonic SN-38 Exposure
type: CreativeWork
description: Statement of the Problem: Irinotecan is used as a single agent or in combination with other drugs to treat metastatic colorectal cancer. However, its usage is largely limited as it exhibits late onset diarrhea in 30-40% of the patient population due to the high accumulation of SN-38 in colon. It has been hypothesized that multiple factors, such as higher biliary excretion of SN-38 and SN-38 glucuronide mediated through different efflux transporters, deglucuronidation of SN-38 glucuronide to SN-38 by bacterial β-glucuronidase secreted by commensal microbiota, generation of toxic active metabolite SN-38 from irinotecan mediated by intestinal carboxylesterse enzymes in gut and enterohepatic recycling of irinotecan and SN-38, etc., can contribute to the elevation of colonic SN-38 content resulting in severe late onset diarrhea. In this particular study, we aimed to investigate the mechanisms that are responsible to reduce the colonic content of SN-38. Towards our goal, three major specific aims were proposed to: (1) develop a modified in situ rat perfusion model for determination of the disposition of irinotecan, SN-38 and SN-38 glucuronide in major metabolic organs and bio-matrices; (2) investigate the potential of certain chemicals and natural products to reduce colonic exposure of SN-38 by inhibiting biliary and intestinal excretions of SN-38 and SN-38 glucuronide employing the modified in situ rat perfusion model; and (3) determine if the selected chemicals and natural products can decrease the colonic exposure of SN-38 by decreasing fecal content of SN-38 employing in vivo pharmacokinetic study. Methods: Surgeries and perfusion experiments were carried out on three different groups of wistar rats (n=4) at different dose of intravenous irinotecan (0.5, 5 and 50 mg/kg) for 150 minutes. Bile, perfusate, urine and plasma were collected at each 30 min interval. Irinotecan, SN-38 and SN-38 glucuronide concentrations from all the collected bio-matrices were quantified by …
abstract: Statement of the Problem: Irinotecan is used as a single agent or in combination with other drugs to treat metastatic colorectal cancer. However, its usage is largely limited as it exhibits late onset diarrhea in 30-40% of the patient population due to the high accumulation of SN-38 in colon. It has been hypothesized that multiple factors, such as higher biliary excretion of SN-38 and SN-38 glucuronide mediated through different efflux transporters, deglucuronidation of SN-38 glucuronide to SN-38 by bacterial β-glucuronidase secreted by commensal microbiota, generation of toxic active metabolite SN-38 from irinotecan mediated by intestinal carboxylesterse enzymes in gut and enterohepatic recycling of irinotecan and SN-38, etc., can contribute to the elevation of colonic SN-38 content resulting in severe late onset diarrhea. In this particular study, we aimed to investigate the mechanisms that are responsible to reduce the colonic content of SN-38. Towards our goal, three major specific aims were proposed to: (1) develop a modified in situ rat perfusion model for determination of the disposition of irinotecan, SN-38 and SN-38 glucuronide in major metabolic organs and bio-matrices; (2) investigate the potential of certain chemicals and natural products to reduce colonic exposure of SN-38 by inhibiting biliary and intestinal excretions of SN-38 and SN-38 glucuronide employing the modified in situ rat perfusion model; and (3) determine if the selected chemicals and natural products can decrease the colonic exposure of SN-38 by decreasing fecal content of SN-38 employing in vivo pharmacokinetic study. Methods: Surgeries and perfusion experiments were carried out on three different groups of wistar rats (n=4) at different dose of intravenous irinotecan (0.5, 5 and 50 mg/kg) for 150 minutes. Bile, perfusate, urine and plasma were collected at each 30 min interval. Irinotecan, SN-38 and SN-38 glucuronide concentrations from all the collected bio-matrices were quantified by …
author: Basu, Sumit
language: eng
keywords: Irinotecan, SN-38, Diarrhea, Rat perfusion, Disposition, Pharmacokinetics
date published: 2015-08
date modified: 2026-07-24T02:32:47Z
provider: University of Houston
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Houston

PropertyValue
property ID: Handle
value: http://hdl.handle.net/10657/2759