A BIOCHEMICAL BASIS FOR THE RENAL ACTIVITY OF N-7-ACETYLCHLOROTHIAZIDE

¹ Merck Institute for Therapeutic Research, West Point, Pennsylvania

The renal responses to large dosages of the N-7-acetyl derivatives of chlorothiazide and hydrochlorothiazide have been interpreted as relating to a low order of saluretic activity in the acetylated compounds, rather than to metabolism in vivo to the corresponding free sulfonamides. We have devised a highly sensitive extraction-chromatography procedure for following the deacylation of N-7-acetylchlorothiazide-3-C¹⁴ in vivo and in in vitro systems derived from renal cortex. Acetylchlorothiazide is actively accumulated by kidney slices and isolated tubules and subsequently deacylated, and a high concentration gradient of the endogenous chlorothiazide is maintained intracellularly. In rabbits, the same sequence of events is observed, resulting in an accumulation of free chlorothiazide within the nephron at a concentration comparable to that obtained upon injection of minimal saluretic dosages of the free thiazide as such.