Cataract development induced by repeated oral dosing with FK506 (tacrolimus) in adult rats.
FK506 (tacrolimus), a potent immunosuppressant, is used for inhibiting allograft rejection in the organ transplantation field. In a preclinical toxicity study in rats, FK506 induced various toxicities, including renal and pancreatic injuries. One of these toxic findings was cataract, and we have found that cataract appeared in rats dosed orally with FK506 for 13 weeks and more. Therefore, to better elucidate the onset mechanism of FK506-induced cataract, we measured biochemical parameters, such as sorbitol, Na,K-ATPase and glutathione in the lens of rats. Rats were dosed with FK506 in oral daily doses of 0.2, 1 or 5 mg/kg for 13 weeks, the lowest dose of which approximated the expected clinical dosage. Cataract developed in the 5-mg/kg/day group, with an incidence of 25%, whereas no cataract formation was observed in the 0.2- or 1-mg/kg/day groups. Five mg/kg/day led an increase of sorbitol and a decrease of reduced type glutathione, but did not affect Na,K-ATPase activity of the lens. FK506 is known to have diabetogenicity mediated through pancreatic injury, which appears as vacuolation of islet cell in rats. Five mg/kg/day of FK506 induced an elevation of blood glucose associated with glucose intolerance, and decrease of both basal insulin level and insulin content in the pancreas, and the changes were in parallel with the cataract development in the present study. On the other hand, diabetic parameters did not change in the 0.2- or 1-mg/kg/day groups. These observation suggest that diabetes developed in the rats dosed with 5 mg/kg/day of FK506. Coadministration of a novel aldose reductase inhibitor, Zenarestat, at an oral dose of 50 mg/kg/day resulted in a reduction of incidence of the FK506-induced cataract and a decrease of sorbitol levels in the lens when compared to that in the lens of rats dosed with 5 mg/kg/day of FK506. These results suggest that FK506-induced cataract in rats is due to an accumulation of sorbitol in the lens, secondary to the diabetogenic effect of FK506. FK506 treatment at the doses of 0.2 and 1 mg/kg/day neither affected parameters indicative of diabetes nor induced cataract in rats, suggesting that the cataract would not develop with FK506 if diabetic parameters were kept under control.
Ishida
H
H
Toxicology Research Laboratories, Fujisawa Pharmaceutical Co. Ltd., Osaka, Japan.
Mitamura
T
T
Takahashi
Y
Y
Hisatomi
A
A
Fukuhara
Y
Y
Murato
K
K
Ohara
K
K
D000284:Administration, Oral; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D002386:Cataract / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005951:Glucose Tolerance Test; D005978:Glutathione / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000633:toxicity*; D007328:Insulin / Q000097:blood; D007908:Lens, Crystalline / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D011799:Quinazolines / Q000494:pharmacology; D051381:Rats; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013012:Sorbitol / Q000378:metabolism; D016559:Tacrolimus / Q000008:administration & dosage / Q000633:toxicity*
D001786:Blood Glucose; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D007328:Insulin; D011799:Quinazolines; C064920:FR 74366; D013012:Sorbitol; D000449:Aldehyde Reductase; D000254:Sodium-Potassium-Exchanging ATPase; D005978:Glutathione; D016559:Tacrolimus