Tissue distribution of the novel DPP-4 inhibitor BI 1356 is dominated by saturable binding to its target in rats

Biopharm Drug Dispos. 2009 Jul;30(5):229-40. doi: 10.1002/bdd.662.


BI 1356 (INN: linagliptin) is an inhibitor of dipeptidyl peptidase-4 (DPP-4). This study investigated whether saturable binding of BI 1356 to its target DPP-4 occurs in tissues and whether drug accumulation occurs at these sites in vivo. In order to test these hypotheses, the tissue distribution of BI 1356 was determined in wild-type and DPP-4 deficient rats at different dose levels by means of whole body autoradiography and measurement of tissue radioactivity concentrations after single i.v. dosing of [(14)C]-radio labeled BI 1356. The accumulation behavior of drug-related radioactivity in tissues was further explored in an oral repeat dose study. Tissue levels of [(14)C]BI 1356 related radioactivity were markedly lower in all investigated tissues of the DPP-4 deficient rats and the difference of the dose-dependent increase of radioactivity tissue levels between both rat strains indicates that tissue distribution at low doses of BI 1356 is dominated by binding of BI 1356 to DPP-4 in tissues. As the binding to DPP-4 is strong but reversible, the tissue binding results in a long terminal half-life in several tissues including plasma. The binding capacity to DPP-4 is, however, limited. In the rat, saturation of DPP-4 binding is suggested at an intravenous dose above 0.01-0.1 mg/kg [(14)C]BI 1356. As the DPP-4 binding capacity is saturated already at low doses, accumulation of BI 1356 in tissues is unlikely, despite the long persistence of low amounts in the body.

MeSH terms

  • Animals
  • Autoradiography
  • Binding Sites
  • Dipeptidyl-Peptidase IV Inhibitors / administration & dosage
  • Dipeptidyl-Peptidase IV Inhibitors / pharmacokinetics*
  • Dose-Response Relationship, Drug
  • Half-Life
  • Linagliptin
  • Male
  • Purines / administration & dosage
  • Purines / pharmacokinetics*
  • Quinazolines / administration & dosage
  • Quinazolines / pharmacokinetics*
  • Rats
  • Rats, Inbred F344
  • Tissue Distribution


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