Urinary tract toxicity in rats following administration of beta(3)-adrenoceptor agonists

ZD7114, [(S)-4-[2-(2-hydroxy-3 phenoxypropylamine)ethoxyl-N-(2-methoxyethyl ) phenoxyacetamide], and ZD2079, [(R)-N-(2-[4-(carboxymethyl)phenoxy]ethyl) -N-(beta-hydroxyphenethyl)ammonium chloride], are beta 3-adrenoceptor stimu lants with selectivity for brown adipose tissue. ZD7144 is the hydrochlorid e salt of the S-enantiomer of the racemic amide ZD2079. They were developed as potential novel treatments for obesity and non-insulin-dependent diabet es mellitus. Male and female rats were dosed separately by gavage for a min imum of 28 days with 0, 10, 50, and 500 mg/kg/day of ZD7114 or with 0, 10, 30, and 150 mg/kg/day of ZD2079. Two further groups of male and female rats were dosed with 0 and 500 mg/kg/day of ZD7114 for 28 days and were then al lowed a 6-wk, undosed withdrawal period. At high doses, both compounds caus ed urinary tract toxicity, which primarily affected the distal tubules and collecting ducts of the kidney via tubular necrosis. They also caused urete ric inflammation, cystitis, and accumulation of crystalline inclusions thro ughout the urinary tract. As a result of urinary tract toxicity, affected a nimals from one or both studies showed reduced red blood cell indices, lowe r platelet counts, and higher white cell counts. Blood chemistry revealed l ower plasma concentrations of glucose (7.28 +/- 1.37 compared to 8.11 +/- 0 .65 for the control) and total protein (63.42 +/- 3.65 compared to 69.17 +/ - 3.24 for the control) and increased plasma urea (37.15 +/- 19.96 compared to 8.09 +/- 0.87 for the control). Urinalysis showed an increase in the nu mber of crystals, blood, and protein. In the urinary tract, the severe crys talluria with accumulation of crystalline material indicated that this may have a role in the etiology of the target organ toxicity. Poor solubility o f the compounds at normal urinary pH was considered a possible mechanism fo r the crystalluria.