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.
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.
Linagliptin (BI 1356) is a novel dipeptidyl peptidase-4 (DPP-4) inhibitor in clinical development for the treatment of type 2 diabetes. It exhibits non-linear pharmacokinetics and shows concentration-dependent plasma protein binding to its target, DPP-4. The aim of this study was to investigate the impact of saturable binding of linagliptin to plasma and tissue DPP-4 by comparing the pharmacokinetics of linagliptin in wildtype and DPP-4 deficient Fischer rats using non-compartmental and model-based data analysis. The non-compartmental analysis revealed a significantly reduced AUC in DPP-4 deficient rats compared with wildtype rats when single intravenous doses
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.
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