Intestinal tract injury by drugs: Importance of metabolite delivery by yellow bile road.
Drug secretion into bile is typically considered a safe route of clearance. However, biliary delivery of some drugs or their reactive metabolites to the intestinal tract evokes adverse consequences due to direct toxic actions or indirect disruption of intestinal homeostasis. Biliary concentration of the chemotherapy agent 5-fluorodeoxyuridine (FUDR) and other compounds is associated with bile duct damage while enterohepatic cycling of antibiotics contributes to the disruptions of gut flora that produce diarrhea. The goal of this review is to describe key evidence that biliary delivery is an important factor in the intestinal injury caused by representative drugs. Emphasis will be given to 3 widely used drugs whose reactive metabolites are plausible causes of small intestinal injury, namely the nonsteroidal anti-inflammatory drug (NSAID) diclofenac, the immunosuppressant mycophenolic acid (MPA), and the chemotherapy agent irinotecan. Capsule endoscopy and other sensitive diagnostic techniques have documented a previously unappreciated, high prevalence of small intestinal injury among NSAID users. Clinical use of MPA and irinotecan is frequently associated such severe intestinal injury that dosage must be reduced. Observations from clinical and experimental studies have defined key events in the pathogenesis of these drugs, including roles for multidrug resistance-associated protein 2 (MRP2) and other transporters in biliary secretion and adduction of enterocyte proteins by reactive acyl glucuronide metabolites as a likely mechanism for intestinal injury. New strategies for minimizing the adverse intestinal consequences of irinotecan chemotherapy illustrate how basic information about key events in the biliary secretion of drugs and the nature of their proximate toxicants can lead to safer protocols for drugs.
Treinen-Moslen
Mary
M
Departments of Pathology and Internal Medicine, University of Texas Medical Branch, 1108 Strand St Building, Room 105, 300 University Boulevard, Galveston, TX 77555-0632, USA. mmolslen@utmb.edu
Kanz
Mary F
MF
D000818:Animals; D000890:Anti-Infective Agents / Q000009:adverse effects; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects; D001646:Bile / Q000378:metabolism*; D001648:Bile Canaliculi / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D003967:Diarrhea / Q000139:chemically induced; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000378:metabolism*
D000890:Anti-Infective Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002352:Carrier Proteins; D004364:Pharmaceutical Preparations