title: Absorption, metabolism and excretion of a single oral dose of (14)C-repaglinide during repaglinide multiple dosing.
abstract: OBJECTIVE
  The present study was designed to assess the disposition of (14)C-repaglinide in whole blood, plasma, urine and faeces, and to measure the total recovery of drug-related material in urine and faeces after a single 2-mg oral dose of (14)C-repaglinide during multiple dosing.
  
  
  METHODS
  In this single-centre, open-label, phase-I trial, six healthy male volunteers received 2 mg of the prandial glucose regulator, repaglinide, four times daily for 13 days, 15 min before meals. On the morning of day 7, breakfast was omitted and the dose was given as an oral solution containing 2 mg of (14)C-repaglinide.
  
  
  RESULTS
  After oral dosing, a mean peak plasma concentration of repaglinide of 27.74 ng. ml(-1) (range: 16.84-36.65 ng. ml(-1)) was observed with a time to peak concentration of 0.5 h. Approximately 20% of repaglinide and its associated metabolites were distributed into red blood cells. No measurable (14)C-radioactivity was present in whole blood samples 6 h after dosing. Within 96 h of dosing with (14)C-repaglinide, 90% of the administered dose appeared in the faeces and 8% was excreted in urine. In the plasma, the major compound was repaglinide (61%). In the urine, the major metabolites were unidentified polar compounds, the aromatic amine (M(1)) (24%), and the dicarboxylic acid (M(2)) (22%). In the faeces, the major metabolite was M(2) (66% of administered dose). Therefore, repaglinide was excreted predominantly as metabolites and the major in vivo metabolite of repaglinide in humans was M(2). During regular dosing for 6 days, the morning plasma trough levels of repaglinide were, with very few exceptions, almost always too low to measure, indicating the absence of accumulation at this dose of 2 mg four times daily. Repaglinide was well tolerated, and there were no episodes of hypoglycaemia.
  
  
  CONCLUSIONS
  After oral dosing with repaglinide, the mean peak plasma concentration was rapidly attained and, thereafter, plasma concentrations decreased promptly. The major route of excretion was via the faeces. These properties make repaglinide a suitable insulin secretagogue for all patients with type-2 diabetes who retain sufficient beta-cell function.
authors.affiliation: Novo Nordisk A/S, Novo Allé, DK-2880 Bagsvaerd, Denmark.
authors.forename: P N
authors.initials: PN
authors.lastname: van Heiningen
authors.forename: V
authors.initials: V
authors.lastname: Hatorp
authors.forename: K
authors.initials: K
authors.lastname: Kramer Nielsen
authors.forename: K T
authors.initials: KT
authors.lastname: Hansen
authors.forename: J J
authors.initials: JJ
authors.lastname: van Lier
authors.forename: N C
authors.initials: NC
authors.lastname: De Merbel
authors.forename: B
authors.initials: B
authors.lastname: Oosterhuis
authors.forename: J H
authors.initials: JH
authors.lastname: Jonkman
mesh_terms: D000042:Absorption; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D002219:Carbamates / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D002250:Carbon Radioisotopes; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D008657:Metabolic Clearance Rate; D010880:Piperidines / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D002219:Carbamates; D002250:Carbon Radioisotopes; D007004:Hypoglycemic Agents; D010880:Piperidines; C072379:repaglinide