Comparison of the rapidity of onset of the therapeutic effect between nateglinide and mitiglinide by PK/PD analysis in rats

  • Toshiyuki Takanohashi
  • Harumi Arisaka
  • Kazuyuki Ubukata
  • Masahiro Hayashi
  • Yasuhiko Yamada
Original Paper


Nateglinide and mitiglinide are immediate short-acting insulinotropic agents. Both are administered preprandially to control postprandial hyperglycemia. Glinide drugs are characterized by immediate onset as well as rapid disappearance of effect as compared with sulfonylurea drugs. We examined the rapidity of onset of the therapeutic effect between nateglinide and mitiglinide by pharmacokinetic/pharmacodynamic analysis using the receptor-binding-dissociation model in rats. Nateglinide or mitiglinide was administered orally or intravenously to rats and blood samples were collected at various time-points post administration. The plasma concentrations of the unbound drug forms and the blood glucose were measured. When the simultaneous fitting of oral administration and intravenous administration was performed using the receptor-binding-dissociation model, the measured values exhibited good correspondence with the fitting curve. Moreover, the time-courses of changes of the receptor-binding rate (sulfonylurea receptor) were examined using the parameters (kon: second-order binding association constant to the receptor, Φ: receptor-binding occupancy ratio) obtained from the analysis. The results showed that the binding rate, which is important for glinide drugs in the early phase after administration, was obviously higher for nateglinide than that for mitiglinide from 10 min after oral administration and between 0 and 30 min after intravenous administration. These results suggest a more rapid onset of the therapeutic effect of nateglinide than that of mitiglinide after the drug is distributed into the blood.


Nateglinide Mitiglinide PK/PD Receptor-binding rate 


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Copyright information

© Springer-Verlag France 2011

Authors and Affiliations

  • Toshiyuki Takanohashi
    • 1
  • Harumi Arisaka
    • 1
  • Kazuyuki Ubukata
    • 1
  • Masahiro Hayashi
    • 2
  • Yasuhiko Yamada
    • 3
  1. 1.Drug Metabolism and Pharmacokinetics, Development Research Laboratories, Research CenterAjinomoto Pharmaceuticals Co., LtdKawasakiJapan
  2. 2.Department of Drug Absorption and PharmacokineticsSchool of Pharmacy, Tokyo University of Pharmacy and Life ScienceHachiojiJapan
  3. 3.Department of Clinical Evaluation of Drug EfficacySchool of Pharmacy, Tokyo University of Pharmacy and Life SciencesHachiojiJapan

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