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Urinary Tract Toxicity in Rats Following Administration of β3-Adrenoceptor Agonists

Safety of Medicines Department, ZENECA Pharmaceuticals, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom

Russell Westwood

Safety of Medicines Department, ZENECA Pharmaceuticals, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom

Gary Nunn

Safety of Medicines Department, ZENECA Pharmaceuticals, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom

Adam Kalinowski

Safety of Medicines Department, ZENECA Pharmaceuticals, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom

Andrew Aldridge

Safety of Medicines Department, ZENECA Pharmaceuticals, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom

ZD7114, [(S)-4-[2-(2-hydroxy-3 phenoxypropylamine)ethoxy]-N-(2-methoxyethyl) phenoxyacetamide], and ZD2079, [(R)-N-(2-[4-(carboxymethyl)phenoxy]ethyl)-N-(β-hydroxyphenethyl)ammonium chloride], are β3-adrenoceptor stimulants with selectivity for brown adipose tissue. ZD7144 is the hydrochloride salt of the S-enantiomer of the racemic amide ZD2079. They were developed as potential novel treatments for obesity and non-insulin-dependent diabetes mellitus. Male and female rats were dosed separately by gavage for a minimum 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 allowed a 6-wk, undosed withdrawal period. At high doses, both compounds caused urinary tract toxicity, which primarily affected the distal tubules and collecting ducts of the kidney via tubular necrosis. They also caused ureteric inflammation, cystitis, and accumulation of crystalline inclusions throughout the urinary tract. As a result of urinary tract toxicity, affected animals from one or both studies showed reduced red blood cell indices, lower platelet counts, and higher white cell counts. Blood chemistry revealed lower 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 number of crystals, blood, and protein. In the urinary tract, the severe crystalluria with accumulation of crystalline material indicated that this may have a role in the etiology of the target organ toxicity. Poor solubility of the compounds at normal urinary pH was considered a possible mechanism for the crystalluria.

Key Words: Kidney • renal • urinary bladder • urinary tract toxicity • β3,-adrenoceptor stimulant

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