title: Pharmacokinetics of nateglinide and its metabolites in subjects with type 2 diabetes mellitus and renal failure.
abstract: OBJECTIVE
  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 m2) 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/l/h; t(1/2) 1.89 h, Cl/F 10.19 l/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.
authors.affiliation: Blood Purification Center, Osaka Medical College, Takatsuki, Osaka, Japan. 1-inoue@poh.osaka-med.ac.jp
authors.forename: T
authors.initials: T
authors.lastname: Inoue
authors.forename: N
authors.initials: N
authors.lastname: Shibahara
authors.forename: K
authors.initials: K
authors.lastname: Miyagawa
authors.forename: R
authors.initials: R
authors.lastname: Itahana
authors.forename: M
authors.initials: M
authors.lastname: Izumi
authors.forename: T
authors.initials: T
authors.lastname: Nakanishi
authors.forename: Y
authors.initials: Y
authors.lastname: Takamitsu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019540:Area Under Curve; D003510:Cyclohexanes / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D000077715:Nateglinide; D010649:Phenylalanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics*; D051437:Renal Insufficiency / Q000097:blood / Q000150:complications*; D013997:Time Factors
chemical_list: D003510:Cyclohexanes; D007004:Hypoglycemic Agents; D000077715:Nateglinide; D010649:Phenylalanine