Concentration-dependent plasma protein binding of the novel dipeptidyl peptidase 4 inhibitor BI 1356 due to saturable binding to its target in plasma of mice, rats and humans

J Pharm Pharmacol. 2009 Jan;61(1):55-62. doi: 10.1211/jpp/61.01.0008.


Objectives: The purpose of this study was to characterise the plasma protein binding of BI 1356.

Methods: BI 1356 (proposed trade name ONDERO) is a novel dipeptidyl peptidase 4 (DPP-4) inhibitor, which is under clinical development for the treatment of type 2 diabetes. DPP-4 is expressed in various tissues but soluble DPP-4 is also present in plasma. Therefore, binding to soluble DPP-4 may influence the pharmacokinetics of BI 1356. Plasma protein binding of BI 1356 was determined in vitro for wild type mice and rats and the results compared with those for DPP-4 knockout mice and DPP-4 deficient Fischer rats. In addition, protein binding of BI 1356 was examined in plasma from healthy human volunteers and renal excretion of the compound in the DPP-4 knockout mice was compared with that occurring in wild type mice.

Key findings: The results showed that BI 1356 exhibited a prominent concentration-dependent plasma protein binding due to a saturable high affinity binding to the DPP-4 target in plasma. Differences in renal excretion of BI 1356 between DPP-4 knockout mice and wild type mice suggested that saturable binding of BI 1356 to DPP-4 in the body also influenced elimination.

Conclusions: High affinity, but readily saturable binding of BI 1356 to its target DPP-4 accounted primarily for the concentration-dependent plasma protein binding at therapeutic plasma concentrations of BI 1356.

MeSH terms

  • Algorithms
  • Animals
  • Diabetes Mellitus, Type 2 / drug therapy
  • Dipeptidyl Peptidase 4 / blood
  • Dipeptidyl Peptidase 4 / genetics
  • Dipeptidyl Peptidase 4 / metabolism*
  • Dipeptidyl-Peptidase IV Inhibitors / chemistry
  • Dipeptidyl-Peptidase IV Inhibitors / metabolism*
  • Dipeptidyl-Peptidase IV Inhibitors / pharmacology
  • Female
  • Humans
  • Kinetics
  • Linagliptin
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Structure
  • Protein Binding
  • Purines / chemistry
  • Purines / metabolism*
  • Purines / pharmacology
  • Quinazolines / chemistry
  • Quinazolines / metabolism*
  • Quinazolines / pharmacology
  • Rats
  • Rats, Inbred F344


  • Dipeptidyl-Peptidase IV Inhibitors
  • Purines
  • Quinazolines
  • Linagliptin
  • Dipeptidyl Peptidase 4