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

Abstract

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

Multidrug Resistance Protein 2 Is an Important Determinant of Paclitaxel Pharmacokinetics

“…However, to date, no compounds are identified that specifically inhibit the transport of lipophilic amphipathic drugs by MRP2. For instance, although for organic anions several studies in rats show that biliary excretion via Mrp2 can be inhibited by probenecid (33,34), we found previously that the in vitro transport of lipophilic amphipathic anticancer drugs and HIV protease inhibitors by MRP2 was rather stimulated in the presence of probenecid (16,30).…”

Transepithelial transport of fluorescent p-glycoprotein and MRP2 substrates by insect Malpighian tubules: confocal microscopic analysis of secreted fluid droplets

“…Although probenecid is a known inhibitor of both MRP2 and also Na + -dependent organic anion transport systems (Horikawa et al, 2002), transport of Texas Red was not reduced in Na + -free saline. In salines containing 5·mol·l -1 Texas Red, the concentration of the dye in the secreted fluid was 92±16·mol·l -1 (N=10) for tubules in control saline and 105±5·mol·l -1 for tubules in Na …”

Involvement of Breast Cancer Resistance Protein (ABCG2) in the Biliary Excretion Mechanism of Fluoroquinolones

“…BSP dissolved in 0.9% saline was infused into a jugular vein through a catheter at a rate of 90.5 mg/h/kg (5 ml/h/kg) throughout the experiments (Horikawa et al, 2002). Twenty minutes after starting the infusion, GPFX was administered at a dose of 1 mg/kg via the jugular vein.…”