Absorption, metabolism and excretion of a single oral dose of C-14-repaglinide during repaglinide multiple dosing

Objective: The present study was designed to assess the disposition of C-14 -repaglinide in whole blood, plasma, urine and faeces, and to measure the t otal recovery of drug-related material in urine and faeces after a single 2 -mg oral dose of C-14-repaglinide during multiple dosing. Methods: In this single-centre, open-label, phase-1 trial, six healthy male volunteers received 2 mg of the prandial glucose regulator, repaglinide, f our 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 C-14-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 a ssociated metabolites were distributed into red blood cells. No measurable C-14-radioactivity was present in whole blood samples 6 h after dosing. Wit hin 96 h of dosing with C-14-repaglinide, 90% of the administered dose appe ared in the faeces and 8% was excreted in urine. In the plasma, the major c ompound was repaglinide (61%). In the urine, the major metabolites were uni dentified polar compounds, the aromatic amine (Mi) (24%), and the dicarboxy lic acid (M-2) (22%). In the faeces, the major metabolite was M2 (66% of ad ministered dose). Therefore, repaglinide was excreted predominantly as meta bolites and the major in vivo metabolite of repaglinide in humans was Mt. D uring regular dosing for 6 days, the morning plasma trough levels of repagl inide were, with very few exceptions, almost always too low to measure, ind icating the absence of accumulation at this dose of 2 mg four times daily. Repaglinide was well tolerated, and there were no episodes of hypoglycaemia . Conclusion: After oral dosing with repaglinide, the mean peak plasma concen tration was rapidly attained and, thereafter, plasma concentrations decreas ed promptly. The major route of excretion was via the faeces. These propert ies make repaglinide a suitable insulin secretagogue for all patients with type-2 diabetes who retain sufficient beta-cell function.