The absorption of 6-mercaptopurine from 6-mercaptopurine riboside in rat small intestine: effect of phosphate

The intestinal absorption of 6-mercaptopurine and its nucleoside 6-mercaptopurine riboside has been studied in the rat with the in situ dual luminal and vascular perfusion. 6-Mercaptopurine is an inactive prodrug that requires intestinal absorption, cellular uptake and intracellular anabolism for cytotoxic activity. Vascular and mucosal samples were analysed by high-performance liquid chromatography (HPLC) to assess the rate of vascular appearance and amounts of thiopurine and its nucleoside in the mucosa. With 5 mmol luminal 6-mercaptopurine/l, the drug is transported across the intestine unchanged at a rate of 0.053±0.006 μmol min−1 (g dry wt.)−1. At concentrations below 20 mmol/l, 6-mercaptopurine riboside is not transported across the intestine intact but is split by phosphorolysis in the intestinal mucosa. The rate of vascular appearance of 6-mercaptopurine [0.043±0.005 μmol min−1 (g dry wt.)−1] from 5 mmol luminal 6-mercaptopurine riboside/l did not differ significantly from that seen with 5 mmol luminal 6-mercaptopurine/l. When the lumen was perfused with 6-mercaptopurine riboside the riboside appeared in the tissue together with a higher mucosal concentration of 6-mercaptopurine than in perfusions with 6-mercaptopurine. Some metabolism of 6-mercaptopurine to 6-thioguanine was also observed; however, no 6-thioguanine appeared in the vascular effluent. Increasing the luminal phosphate concentration from 2 to 10 mmol/l increased mucosal phosphorolysis of 6-mercaptopurine riboside and more than tripled the rate of vascular appearance of 6-mercaptopurine; conversion of 6-mercaptopurine to 6-thioguanine was significantly inhibited. These results suggest that with a modest increase in luminal phosphate concentration, 6-mercaptopurine riboside can be a more effective substrate than the free drug for the oral delivery of 6-mercaptopurine.