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Tissue distribution of the novel DPP‐4 inhibitor BI 1356 is dominated by saturable binding to its target in rats
Author(s) -
Fuchs Holger,
Binder Rudolf,
Greischel Andreas
Publication year - 2009
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.662
Subject(s) - in vivo , medicine , endocrinology , distribution (mathematics) , linagliptin , chemistry , biophysics , pharmacology , enzyme inhibitor , biology , enzyme , biochemistry , mathematical analysis , microbiology and biotechnology , mathematics , diabetes mellitus , type 2 diabetes mellitus
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. Copyright © 2009 John Wiley & Sons, Ltd.