Urothelial hyperplasia induced by carbonic anhydrase inhibitors (CAIs) in animals and its relationship to urinary Na and pH.
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.
Durand-Cavagna
G
G
Merck Sharp & Dohme-Chibret Laboratories, Department of Safety Assessment, Riom, France.
Owen
R A
RA
Gordon
L R
LR
Peter
C P
CP
Boussiquet-Leroux
C
C
D000086:Acetazolamide / Q000633:toxicity; D000818:Animals; D002257:Carbonic Anhydrase Inhibitors / Q000633:toxicity*; D004285:Dogs; D005260:Female; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D006965:Hyperplasia / Q000139:chemically induced / Q000473:pathology; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D012964:Sodium / Q000652:urine*; D013449:Sulfonamides / Q000633:toxicity; D013876:Thiophenes / Q000633:toxicity; D001743:Urinary Bladder / Q000473:pathology; D001745:Urinary Bladder Diseases / Q000139:chemically induced* / Q000473:pathology
D002257:Carbonic Anhydrase Inhibitors; D013449:Sulfonamides; D013876:Thiophenes; D012964:Sodium; C057921:sezolamide; D000086:Acetazolamide