Pharmacokinetics of nateglinide and its metabolites in subjects with type 2 diabetesmellitus and renal failure

Aims: We evaluated the benefits and safety of nateglinide, a novel oral hypoglycemic agent, in type 2 diabetes patients with renal failure. Methods: Single-dose pharmacokinetics were studied in 8 patients with type 2 diabetes and a low creatinine clearance (range 1.8 - 16.5 ml/min/1.73 m(2)) up to 6 hours after 90 mg nateglinide administration. Next, we treated another group of 8 patients undergoing regular hemodialysis with nateglinide 90 mg/day for 1 - 3 months. The effect of hemodialysis on metabolite accumulation was then tested. Results: After a single 90 mg dose, nateglinide significantly increased the post-prandial secretion of insulin and thereby reduced plasma glucose levels. Mean pharmacokinetic parameters (AUC(0-6) 10.45 mg/Uh; t(1/2) 1.89 h, Cl/F 10.19 1/h) were comparable with those reported in healthy subjects. A much larger AUC value than those previously reported of M1, a major metabolite in the urine of healthy subjects, was observed, and the plasma concentration of M1 did not decline up to 6 hours after. In patients treated on a regular basis, there was marked accumulation of M1, while nateglinide could not be detected 24 hours after the last dose. Plasma M1 levels were significantly reduced by the hemodialysis sessions. Conclusions: Single 90 mg dose of nateglinide was safe and effective in patients with renal failure. However, repeated administrations could cause prolonged hypoglycemia due to accumulation of M1, which is known to have a modest hypoglycemic activity. Hemodialysis may help to eliminate excessive accumulation of M1.