1. The transport of 6-thioguanine and 6-mercaptopurine has been studied with isolated jejunal loops of mouse small intestine. H.p.l.c. was used to identify and quantify the thiopurines and their metabolites in the serosal secretions. 2. When the lumen of the intestinal loops contained either 6-thioguanine or 6-mercaptopurine at a concentration of 1 mmol/l, the concentration of unmetabolized drug in the serosal secretions reached a maximum of 0.13 ± 0.02 mmol/l (mean ± sem ). 3. Analysis of the serosal secretions from the perfusions with either of the drugs revealed the appearance of an unknown compound which had the characteristics of a thiopurine and the same time course of appearance as the unmetabolized drug. Thus 6-thioguanine and 6-mercaptopurine are significantly metabolized during absorption in mouse intestine. 4. The unknown compound was identified as 6-thiouric acid, and with 1 mmol/l 6-thioguanine or 6-mercaptopurine in the lumen the concentration of this metabolite in the serosal secretions rose to a maximum of 0.13 ± 0.01 and 0.18 ± 0.03 mmol/l, respectively. At luminal drug concentrations of 0.1 mmol/l, the metabolite accounted for approximately 90% of the serosal thiopurine. 5. After an initial lag period of 20 min, linear rates of appearance in the serosal secretions were obtained for both the unmetabolized drugs and 6-thiouric acid. 6. Addition of the xanthine oxidase inhibitor oxypurinol at a luminal concentration of 0.3 mmol/l prevented the formation of 6-thiouric acid from 6-thioguanine. However, the inhibitor reduced the rate of 6-thioguanine appearance in the serosal secretions by 50%. 7. The conversion of 6-mercaptopurine to 6-thiouric acid was prevented when allopurinol or oxypurinol were added to the lumen. At a luminal drug concentration of 1 mmol/l, allopurinol increased the rate at which 6-mercaptopurine appeared in the serosal secretions by 90% compared with an increase of only 50% with oxypurinol. 8. The transport of water and glucose by the mouse intestinal loops was unaffected by 6-thioguanine or the xanthine oxidase inhibitors. However, 6-mercaptopurine caused significant reductions in the rate of water transport (30%) and glucose transport (39%). These effects were observed at a luminal drug concentration of 0.1 mmol/l and there was no further increase at a drug concentration of 1 mmol/l.
1. The transport of 5-fluorouracil, uracil and thymine has been studied with isolated jejunal loops of rat small intestine. High performance liquid chromatography was used to identify the pyrimidines and measure their concentrations. 2. When the lumen of the intestine was perfused with 5-fluorouracil or uracil at 0.1 mmol/l or 0.2 mmol/l, the concentration in the serosal secretions was significantly higher than that in the lumen. For thymine the serosal concentration exceeded that in the lumen only at 0.1 mmol/l. 3. Analysis of the mucosal tissue water at the end of the perfusion demonstrated that when the intestinal lumen was perfused with any one of the three pyrimidines at 0.1 mmol/l or 0.2 mmol/l the concentration within the tissue was significantly above that in the lumen. 4. After an initial lag period linear rates of transport from the lumen to the serosal secretions were obtained for all three pyrimidines over a 10-fold concentration range from 0.1 mmol/l to 1 mmol/l. 5. Uracil and thymine inhibited the transmural transport of 5-fluorouracil. 6. The transport of 5-fluorouracil was also studied with a vascularly perfused preparation of rat small intestine. At 0.1 mmol/l the rate of transmural transport of the drug in this preparation was substantially higher than in the jejunal loops. This difference was eliminated by adding 5-fluorouracil to the vascular perfusate, suggesting that the higher transport rate in the vascularly perfused preparation was due to the lower serosal drug concentrations in the mesenteric circulation of the perfused intestine. 7. At a concentration of 5 mmol/l 5-fluorouracil inhibited water transport in the isolated loops and transmural D-galactose transport in the vascular perfusions.