Transporter and metabolic enzyme-mediated intra-enteric circulation of SN-38, an active metabolite of irinotecan: A new concept

SN-38, an active metabolite of irinotecan (CPT-11), is thought to circulate enterohepatically via organic anion-transporting polypeptides (OATPs), UDP-glucuronyl transferases (UGTs), multidrug resistance-related protein 2 (MRP2), and breast cancer resistance protein (BCRP). These transporters and enzymes are expressed in not only hepatocytes but also enterocytes. Therefore, we hypothesized that SN-38 circulates between the intestinal lumen and the enterocytes via these transporters and metabolic enzymes. To test this hypothesis, metabolic and transport studies of SN-38 and its glucuronide (SN-38G) were conducted in Caco-2 cells. The mRNA levels of UGTs, MRP2, BCRP, and OATP2B1 were confirmed in Caco-2 cells. SN-38 was converted to SN-38G in Caco-2 cells. The efflux of intracellularly generated SN-38G across the apical (digestive tract) membranes was significantly higher than the efflux across the basolateral (blood, portal vein) membranes of Caco-2 cells cultured on polycarbonate membranes. SN-38G efflux to the apical side was significantly reduced in the presence of MRP2 and BCRP inhibitors, suggesting that SN-38G is transported across the apical membrane by MRP2 and BCRP. Treatment of Caco-2 cells with OATP2B1 siRNA increased the SN-38 residue on the apical side, confirming that OATP2B1 is involved in the uptake of SN-38 into enterocytes. No SN-38 was detected on the basolateral side with or without siRNA treatment, suggesting that the enterohepatic circulation of SN-38 is limited, contrary to previous reports. These results suggest that SN-38 is absorbed into the enterocytes via OATP2B1, glucuronidated by UGTs to SN-38G, and excreted into the digestive tract lumen by MRP2 and BCRP. SN-38G can be deconjugated by β-glucuronidase from intestinal bacteria in the digestive tract lumen to regenerate SN-38. We named this new concept of local drug circulation "intra-enteric circulation." This mechanism may allow SN-38 to circulate in the intestine and cause the development of delayed diarrhea, a serious side effect of CPT-11.