Novel Agents that Potentially Inhibit Irinotecan-Induced Diarrhea

Abstract

Irinotecan (CPT-11, 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin) has exhibited clinical activities against a broad spectrum of carcinomas by inhibiting DNA topoisomerase I (Topo I). However, severe and unpredictable dosing-limiting toxicities (mainly myelosuppression and severe diarrhea) hinder its clinical use. The latter consists of early and late-onset diarrhea, occurring within 24 hr or > or = 24 hr after CPT-11 administration, respectively. This review highlights novel agents potentially inhibiting CPT-11-induced diarrhea, which are designed and tested under guidance of disposition pathways and potential toxicity mechanisms. Early-onset diarrhea is observed immediately after CPT-11 infusion and probably due to the inhibition of acetylcholinesterase activity, which can be eliminated by administration of atropine. Late-onset diarrhea appears to be associated with intestinal exposure to SN-38 (7-ethyl-10-hydroxycamptothecin), the major active metabolite of CPT-11, which may bind to Topo I and induce apoptosis of intestinal epithelia, leading to the disturbance in the absorptive and secretory functions of mucosa. CPT-11 and SN-38 may also stimulate the production of pro-inflammatory cytokines and prostaglandins (PGs), thus inducing the secretion of Na(+) and Cl(-). Early treatment of severe late-onset diarrhea with oral high-dose loperamide has decreased patient morbidity. Extensive studies have been conducted to identify other potential agents to ameliorate diarrhea in preclinical and clinical models. These include intestinal alkalizing agents, oral antibiotics, enzyme inducers, P-glycoprotein (PgP) inhibitors, cyclooxygenase-2 (COX-2) inhibitors, tumor necrosis factor-alpha (TNF-alpha) inhibitors, or blockers of biliary excretion of SN-38. Further studies are needed to identify the molecular targets associated with CPT-11 toxicity and safe and effective agents for alleviating CPT-11-induced diarrhea.

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

“…And since the intestinal exposure to SN-38 in the gut was associated with the development of severe toxicity manifested as drug induced diarrhea [3,4], we suggested that quantifying the level of SN-38 that is exsorbed following intestinal perfusion of irinotecan shall be a good indicator for predicting irinotecan induced intestinal toxicity that results from drug administration.…”

“…It is an ester prodrug that is biotransformed in vivo to its cytotoxic metabolite SN-38 by the action of carboxylesterase (1,2). SN-38 is conjugated to form SN-38-glucuronide to be excreted via bile to the intestines, where it can be hydrolyzed back to SN-38 by the action of enterobacterial B-glucuronidase (3,4); Figure 1 shows the chemical structures of irinotecan and SN-38.…”

“…Both CPT-11 and SN-38 exist in pH dependent equilibrium between their lactone form (pharmacologically active form) in acidic media and open ring carboxylate form in alkaline media (6). Drug induced intestinal toxicity manifested as severe diarrhea is a main side effect of irinotecan found to hinder its clinical benefits (3). The intestinal toxic effect of irinotecan was shown to be associated with the intestinal exposure to the active metabolite SN-38 either by biliary excretion of SN-38 glucuronide or by intestinal excretion (3,4).…”

“…Drug induced intestinal toxicity manifested as severe diarrhea is a main side effect of irinotecan found to hinder its clinical benefits (3). The intestinal toxic effect of irinotecan was shown to be associated with the intestinal exposure to the active metabolite SN-38 either by biliary excretion of SN-38 glucuronide or by intestinal excretion (3,4). Drug efflux transporters mainly (p-gp) play a major role in the disposition of both CPT-11 and SN-38 (7), thus, inhibition of those intestinal efflux pumps would be a rational way to improve oral bioavailability and ameliorate intestinal toxicity of irinotecan, due to the potential of these inhibitors such as verapamil to inhibit the exsorption of both irinotecan and SN-38 to the lumen of the gut (5).…”

Is human placenta proteoglycan remodeling involved in pre-eclampsia?

“…Despite an increased understanding of the roles of PGs in processes at the cell surface and in the extracellular matrix (ECM) during the early part of the last decade [9,10], little is known about the placental structure of GAGs as contributing variables in the development of pre-eclampsia. PGs are distributed in placenta endothelium, cell basement membranes, vessel walls, and villous stroma [11,12,13]. Detailed characterizations indicate the placental basement membrane tissue predominantly contains HS PGs, whereas CS/DS PGs are mainly located in the intervillous space of the ECM [14].…”