Titre du document / Document title

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

Auteur(s) / Author(s)

VAN HEININGEN P. N. M. ⁽¹⁾ ; HATORP V. ⁽²⁾ ; NIELSEN K. K. ⁽²⁾ ; HANSEN K. T. ⁽²⁾ ; VAN LIER J. J. ⁽¹⁾ ; DE MERBEL N. C. V. ⁽¹⁾ ; OOSTERHUIS B. ⁽¹⁾ ; JONKMAN J. H. G. ⁽¹⁾ ;

Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)

⁽¹⁾ Pharma Bio-Research International B.V., Zuidlaren, PAYS-BAS
⁽²⁾ Novo Nordisk A/S, Novo Allé, 2880 Bagsvaerd, DANEMARK

Résumé / Abstract

Objective: The present study was designed to assess the disposition of ¹⁴C-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 ¹⁴C-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 ¹⁴C-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 ¹⁴C-redioactivity was present in whole blood samples 6 h after dosing. Within 96 h of dosing with ¹⁴C-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 (M₁) (24%), and the dicarboxylic acid (M₂) (22%). In the faeces, the major metabolite was M₂ (66% of administered dose). Therefore, repaglinide was excreted predominantly as metabolites and the major in vivo metabolite of repaglinide in humans was M₂. 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. Conclusion: 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 β-cell function.

Revue / Journal Title

European journal of clinical pharmacology   ISSN 0031-6970 

Source / Source

1999, vol. 55, n^o7, pp. 521-525 (7 ref.)

Langue / Language

Anglais

Editeur / Publisher

Springer, Berlin, ALLEMAGNE  (1970) (Revue)

Mots-clés anglais / English Keywords

Repaglinide ; Hypoglycemic agent ; Oral administration ; Tablet ; Single dose ; Multiple dose ; Long term ; Non insulin dependent diabetes ; Healthy subject ; Clinical trial ; Blood plasma ; Blood ; Urine ; Feces ; Metabolite ; Toxicity ; Pharmacokinetics ; Human ; Endocrinopathy ;

Mots-clés français / French Keywords

Répaglinide ; Hypoglycémiant ; Voie orale ; Comprimé ; Dose unique ; Dose répétée ; Long terme ; Diabète non insulinodépendant ; Individu sain ; Essai clinique ; Plasma sanguin ; Sang ; Urine ; Fèces ; Métabolite ; Toxicité ; Pharmacocinétique ; Homme ; Endocrinopathie ;

Mots-clés espagnols / Spanish Keywords

Repaglinida ; Hipoglicemiante ; Vía oral ; Tableta ; Dosis única ; Dosis múltiple ; Largo plazo ; Diabetes no insulinodependiente ; Individuo sano ; Ensayo clínico ; Plasma sanguíneo ; Sangre ; Orina ; Heces ; Metabolito ; Toxicidad ; Farmacocinética ; Hombre ; Endocrinopatía ;

Localisation / Location

INIST-CNRS, Cote INIST : 13739, 35400008994791.0060