title: The absorption of 6-mercaptopurine from 6-mercaptopurine riboside in rat small intestine: effect of phosphate.
abstract: 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 mumol 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 mumol 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.
authors.affiliation: Department of Biology, University of York, UK.
authors.forename: A M
authors.initials: AM
authors.lastname: Pennington
authors.forename: J R
authors.initials: JR
authors.lastname: Bronk
mesh_terms: D000818:Animals; D066298:In Vitro Techniques; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000098:blood supply / Q000378:metabolism*; D007421:Intestine, Small / Q000098:blood supply / Q000378:metabolism*; D007583:Jejunum / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D015122:Mercaptopurine / Q000378:metabolism* / Q000493:pharmacokinetics; D010477:Perfusion; D011355:Prodrugs / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow; D013868:Thioinosine / Q000378:metabolism*; D013997:Time Factors; D014527:Uric Acid / Q000032:analysis
chemical_list: D011355:Prodrugs; D014527:Uric Acid; D013868:Thioinosine; D015122:Mercaptopurine