Intestinal absorption and metabolism of 6-mercaptopurine in the rat small intestine.

The intestinal absorption of 6-mercaptopurine was examined in the rat by in vitro and in situ techniques for the purpose of establishing absorption characteristics which might explain the poor systemic oral availability of this drug. Experiments were designed to evaluate the significance of intestinal metabolism and active secretion processes. Since mucosal/serosal drug concentration gradients across in vitro segments were not significantly different (P greater than 0.05) for everted and noneverted preparations, with values of 1.21 +/- 0.27 and 0.91 +/- 0.12, respectively, it was concluded that active secretion or absorption mechanisms were absent. Varying the concentration of 6-mercaptopurine from 0.24 to 5.88 mM demonstrated saturability of the biotransformation of 6-mercaptopurine to 6-thiouric acid with a maximum rate of 1.6 X 10(-5) mmoles per min g for jejunal portions. Distal segments displayed 85% higher rates of biotransformation at concentrations of 1.47 mM. Inclusion of allpurinol (2 mM) completely inhibited biotransformation. With in situ loops perfused with 1.47 mM drug, collection of mesentery blood showed that absorption rates of 6-thiouric acid were 0.67 that of the parent drug.