This Article Abstract Free Full Text (Free PDF) Free Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by Waghe, M. Articles by Aldridge, A. Search for Related Content PubMed PubMed Citation Articles by Waghe, M. Articles by Aldridge, A. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB UREA Social Bookmarking                         What's this?

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

References

• Corrado ML, Struble WE, Peter C., Hoagland V., and Sabbaj J. (1987). Norfolaxin: Review of safety studies. Am. J. Med. 82(suppl 6B): 22-26.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Cox B. and Holloway BR (1992). Compound profile document for non-shivering thermogenesis project: Selective β3-adrenoceptor agonist: ZD2079, Internal Report. Zeneca Pharmaceuticals, Cheshire, United Kingdom.
• Farebrother DA (1984). Histopathological changes found in the renal medulla of rats in adenine toxicity. In: Renal Heterogeneity and Target Cell Toxicity, PH Bach and EA Lock (eds). John Wiley & Sons, Chichester, United Kingdom, pp. 223-226.
• Glaister JR (1986). Target organ pathology. In: Principles of Toxicological Pathology, Taylor and Francis, London, pp. 101-102. 5. Holloway BR, Howe R., Rao BS, Stribling D., Mayers RM, Briscoe MG, and Jackson MJ (1991). ICI D7114 a novel selective β-adrenoceptor agonist selectively stimulates brown fat and increases whole-body oxygen consumption. Br. J. Pharmacol. 104: 97-104.[Web of Science][Medline] [Order article via Infotrieve]
• Kalinowski AE (1994). ZENECA ZD2079: Investigation of kidney toxicity in the rat, oral administration, Internal Report. Zeneca Pharmaceuticals, Cheshire, United Kingdom.
• Mayer DG (1987). The safety profile of afloxacin in drug interaction studies. Overview of toxicological studies. Drugs 34(suppl 1): 150-153.[Web of Science][Medline] [Order article via Infotrieve]
• Stock MJ and Rothwell NJ (1985). Factors influencing brown fat and the capacity for diet-induced thermogenesis. Int. J. Obes. 9(suppl 2): 9-15.[Web of Science][Medline] [Order article via Infotrieve]
• Stribling D. (1988). Metabolic dysfunction project team report: Non-shivering thermogenesis (Brown fat), Internal Report. Zeneca Pharmaceuticals, Cheshire, United Kingdom.
• Tucker WE Jr, Macklin AW, Szot RJ, Johnston RE, Elion GB, de Miranda P., and Szczech GM (1983). Preclinical toxicity studies with acyclovir: Acute and subchronic tests. Fundam. Appl. Toxicol. 3: 573-578.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Zbinden G. (1969). Experimental renal toxicity. In: The Kidney, Morphology, Biochemistry, Physiology, Vol. 2, C Rouiller and AF Muller (eds). Academic Press, New York, pp. 401-475.

Toxicologic Pathology, Vol. 27, No. 2, 165-170 (1999)
DOI: 10.1177/019262339902700203


CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?

This Article Abstract Free Full Text (Free PDF) Free Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by Waghe, M. Articles by Aldridge, A. Search for Related Content PubMed PubMed Citation Articles by Waghe, M. Articles by Aldridge, A. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB UREA Social Bookmarking                         What's this?