Renal metabolism of sulindac: functional implications.

We examined the metabolism of the prodrug sulindac sulfoxide and the active moiety, sulindac sulfide, in the isolated perfused kidney of the rabbit. Whether the sulfoxide or the sulfide was infused did not affect notably the pattern of drug efflux. In either case, the inactive sulfoxide and sulfone were the only forms recovered from urinary or venous effluents except for the appearance of a small amount of sulfide in the venous effluent after infusion of the sulfide. In contrast, large amounts of the sulfide were recovered from renal tissue, in addition to the inactive forms, after either prodrug or sulfide administration. We also examined the effects of the prodrug and the sulfide on stimulated release of prostaglandins in response to angiotensin II in the rabbit kidney and to norepinephrine in the rat kidney. Infusion of either 1 microgram/ml of sulindac sulfide or 10 micrograms/ml of sulfoxide inhibited prostaglandin release from both rabbit and rat kidneys. Inclusion of 2% bovine serum albumin in the perfusing medium largely confined radiolabeled forms of sulindac to the vascular space and inhibited oxidative inactivation of sulindac sulfide. However, inhibition of prostaglandin release by sulindac sulfide was only slightly reduced by protein binding. We conclude that 1) the kidney rapidly interconverts sulfide and sulfoxide forms; 2) the forms of sulindac present in renal tissue contrast with the inactive forms recovered from urinary and venous effluents; 3) either prodrug or sulfide administration can result in renal cyclooxygenase inhibition; and 4) protein binding restricts sulindac sulfide primarily to the vascular compartment but does not prevent inhibition of prostaglandin synthesis.