© 1992 Oxford University Press
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Urothelial Hyperplasia Induced by Carbonic Anhydrase Inhibitors (CAIs) in Animals and Its Relationship to Urinary Na and pH
Merck Sharp & Dohme-Chibret Laboratories, Research Center, Department of Safety Assessment B.P. 134, Route de Marsat, 63203 Riom, France; *Department of Safety Assessment, Merck Sharp & Dohme Research Laboratories West Point, Pennsylvania 19486
Received April 4, 1991; accepted July 19, 1991
Urothelial Hyperplasia Induced by Carbonic Anhydrase Inhibitors (CAIs) in Animals and Its Relationship to Urinary Na and pH. DURAND-CAVAGNA, G., OWEN, R. A., GORDON, L. R., PETER, C. P., AND BOUSSIQUET-LEROUX, C. (1992). Fundam. Appl. Toxicol. 18, 137–143.
Investigations of MK-0927 and acetazolamide, both carbonic anhydrase inhibitors (CAIs), showed that urothelial hyperplasia develops in rats and mice, but not in rabbits, dogs, or monkeys. Rats given MK-0927 orally had a rapid onset of the change which regresses often completely despite continued treatment. Increased urinary pH and Na excretion, pharmacologic effects of CAIs, tended to be correlated with lesions. Rats given MK-0927 orally and fed either a 5% potassium phosphate meal or a 5% ammonium chloride meal had reduced urinary pH and/or urinary Na excretion and a reduced incidence of urothelial hyperplasia. Rats given MK-0927 orally and fed a low Na diet had very low urinary Na and essentially no urothelial hyperplasia. It was concluded that a clear relation exists between increased urinary Na excretion and pH, and urothelial hyperplasia induced by CAIs. These results in rats confirm the importance of increased Na and pH as stimuli for the development of urothelial hyperplasia.