Carcinogenicity in rats of the SGLT2 inhibitor canagliflozin
Autor: | Petra Vinken, Sandra De Jonghe, Jim Proctor, Mark D. Johnson, Bianca Feyen, Dirk Mariën, Helena Geys, Inneke Wynant, Rao N.V.S. Mamidi |
---|---|
Rok vydání: | 2014 |
Předmět: |
Male
endocrine system medicine.medical_specialty Carcinogenesis Carcinogenicity Tests Adrenal Gland Neoplasms chemistry.chemical_element Parathyroid hormone Pheochromocytoma Thiophenes Calcium Toxicology Rats Sprague-Dawley Structure-Activity Relationship Glucosides Sodium-Glucose Transporter 2 Testicular Neoplasms Internal medicine medicine Animals Canagliflozin Sodium-Glucose Transporter 2 Inhibitors Calcium metabolism Kidney Dose-Response Relationship Drug Leydig cell Chemistry General Medicine Kidney Neoplasms Urinary calcium Rats Kidney Tubules medicine.anatomical_structure Endocrinology SGLT2 Inhibitor Luteinizing hormone Leydig Cell Tumor |
Zdroj: | Chemico-Biological Interactions. 224:1-12 |
ISSN: | 0009-2797 |
Popis: | The carcinogenicity potential of canagliflozin, an inhibitor of SGLT2, was evaluated in a 2-year rat study (10, 30, and 100 mg/kg). Rats showed an increase in pheochromocytomas, renal tubular tumors, and testicular Leydig cell tumors. Systemic exposure multiples at the highest dose relative to the maximum clinical dose were 12- to 21-fold. Pheochromocytomas and renal tubular tumors were noted in both sexes at 100 mg/kg. Leydig cell tumors were observed in males in all dose groups and were associated with increased luteinizing hormone levels. Hyperplasia was increased in the adrenal medulla at 100 mg/kg, but only a limited increase in simple tubular hyperplasia was observed in the kidney of males at 100 mg/kg. Hyperostosis occurred and was accompanied by substantial effects on calcium metabolism, including increased urinary calcium excretion and decreased levels of calcium regulating hormones (1,25-dihydroxyvitamin D and parathyroid hormone). A separate study with radiolabeled calcium confirmed that increased urinary calcium excretion was mediated via increased calcium absorption from the gastrointestinal tract. It was hypothesized that, at high doses, canagliflozin might have inhibited glucose absorption in the intestine via SGLT1 inhibition that resulted in glucose malabsorption, which increased calcium absorption by stimulating colonic glucose fermentation and reducing intestinal pH. Pheochromocytomas and adrenal medullary hyperplasia were attributed to altered calcium homeostasis, which have a known relationship in the rat. In conclusion, Leydig cell tumors were associated with increased luteinizing hormone levels and pheochromocytomas were most likely related to glucose malabsorption and altered calcium homeostasis. Renal tubular tumors may also have been linked to glucose malabsorption. |
Databáze: | OpenAIRE |
Externí odkaz: |