Nephrotoxicity of pravadoline maleate (WIN 48098-6) in dogs: evidence of maleic acid-induced acute tubular necrosis
| Autor: | Susan J. Ward, Raymond M. Everett, Michel Rollin, Yigal Greener, Gérard Descotes, David P. Benziger, James C. Bradford |
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| Rok vydání: | 1993 |
| Předmět: |
Male
medicine.medical_specialty Pravadoline Indoles Maleic acid Pharmacology Motor Activity Toxicology Nephrotoxicity chemistry.chemical_compound Dogs Oral administration Internal medicine medicine Animals Acute tubular necrosis Chemistry Maleates Kidney Tubular Necrosis Acute medicine.disease Endocrinology Toxicity Pharmaceutics Ataxia Female Acid–base reaction |
| Zdroj: | Fundamental and applied toxicology : official journal of the Society of Toxicology. 21(1) |
| ISSN: | 0272-0590 |
| Popis: | Single oral administration of pravadoline maleate (WIN 48098-6), the maleic acid salt of WIN 48098, induced acute tubular necrosis (ATN) in male and female beagle dogs at dosages > or = 40 mg/kg (WIN 48098 base (31 mg/kg) and maleic acid (9 mg/kg)). Subsequent oral studies were conducted with equimolar dosages of maleic acid and WIN 48098-7, the ethanesulfonate salt of WIN 48098, to determine the nephrotoxic moiety of WIN 48098-6. ATN was observed for dogs given only maleic acid at single oral dosages > or = 9 mg/kg. This result provided evidence that maleic acid was responsible for the nephrotoxicity observed in dogs given single oral dosages of WIN 48098-6. The induction of maleic acid-related nephrotoxicity in dogs may confound the interpretation of toxicologic studies of maleic acid salts of basic pharmaceutics, if the dosage of test article results in the delivery of dosages of maleic acid > or = 9 mg/kg. Furthermore, the results of these studies underscore the importance of establishing maximum no-observed-effect dosages and target organ toxicity profiles for acids and bases that are commonly used in the development of salts of pharmaceutics. |
| Databáze: | OpenAIRE |
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