The Potential for an Interaction between MRP2 (ABCC2) and Various Therapeutic Agents: Probenecid as a Candidate Inhibitor of the Biliary Excretion of Irinotecan Metabolites

摘要: Irinotecan hydrochloride (CPT-11) is an anticancer agent with unpredictable bouts of diarrhea as a dose-limiting toxic side-effect. Since the biliary excretion its active metabolite (SN-38) and SN-38 glucuronide (SN38-Glu), which are mediated by multidrug resistance associated protein-2 (MRP2/ABCC2), has been proposed to be related this gastrointestinal toxicity, we have attempted here examine potential various therapeutic agents interact in order identify MRP2 inhibitors prevent toxicity. The inhibition constants (K(i)) 26 compounds were examined for transport typical substrate isolated canalicular membrane vesicles. Of these, 13 inhibited K(i) values from 0.0461 281 microM. Three (probenecid, sulfobromophthalein glycyrrhizin) also found inhibit SN38-Glu rats vivo, degrees compatible estimated based on ratios unbound concentrations circulating plasma. A similar estimation inhibitory effect human was considering both each concentration plasma inlet liver. predicted most minimal whereas approximately 75% probenecid. Thus, probenecid may candidate can used clinically CPT-11 metabolites, interaction between other more unlikely.