Renal tubular and adrenal medullary tumors in the 2-year rat study with canagliflozin confirmed to be secondary to carbohydrate (glucose) malabsorption in the 15-month mechanistic rat study
| Autor: | Godelieve Lammens, Bianca Feyen, Petra Vinken, Jim Proctor, Mark D. Johnson, Rao N.V.S. Mamidi, Sandra De Jonghe |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine medicine.medical_specialty Malabsorption Adrenal Gland Neoplasms Toxicology Rats Sprague-Dawley 03 medical and health sciences 0302 clinical medicine Dietary Sucrose Internal medicine medicine Animals Hypoglycemic Agents Canagliflozin Kidney Leydig cell business.industry General Medicine Hyperplasia medicine.disease Kidney Neoplasms Rats Glucose Kidney Tubules 030104 developmental biology medicine.anatomical_structure Endocrinology Glucose-galactose malabsorption 030220 oncology & carcinogenesis SGLT2 Inhibitor business Adrenal medulla medicine.drug |
| Zdroj: | Chemico-Biological Interactions. 277:85-90 |
| ISSN: | 0009-2797 |
| Popis: | During preclinical development of canagliflozin, an SGLT2 inhibitor, treatment-related pheochromocytomas, renal tubular tumors (RTT), and testicular Leydig cell tumors were reported in the 2-year rat toxicology study. In a previous 6-month rat mechanistic study, feeding a glucose free diet prevented canagliflozin effects on carbohydrate malabsorption as well as the increase in cell proliferation in adrenal medulla and kidneys, implicating carbohydrate malabsorption as the mechanism for tumor formation. In this chronic study male Sprague-Dawley rats were dosed orally with canagliflozin at high dose-levels (65 or 100 mg/kg/day) for 15 months and received either a standard diet or a glucose-free diet. Canagliflozin-dosed rats on standard diet showed presence of basophilic renal tubular tumors (6/90) and an increased incidence of adrenal medullary hyperplasia (35/90), which was fully prevented by feeding a glucose-free diet (no RTT's; adrenal medullary hyperplasia in ≤5/90). These data further confirm that kidney and adrenal medullary tumors in the 2-year rat study were secondary to carbohydrate (glucose) malabsorption and were not due to a direct effect of canagliflozin on these target tissues. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect