Tissue distribution of the novel DPP-4 inhibitor BI 1356 is dominated by saturable binding to its target in rats.
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.
Fuchs
Holger
H
Boehringer Ingelheim Pharma GmbH & Co. KG, Department of Drug Metabolism and Pharmacokinetics, Birkendorfer Str. 65, 88397 Biberach/Riss, Germany. holger.fuchs@boehringer-ingelheim.com
Binder
Rudolf
R
Greischel
Andreas
A
D000818:Animals; D001345:Autoradiography; D001665:Binding Sites; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D000069476:Linagliptin; D008297:Male; D011687:Purines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011799:Quinazolines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D011916:Rats, Inbred F344; D014018:Tissue Distribution
D054873:Dipeptidyl-Peptidase IV Inhibitors; D011687:Purines; D011799:Quinazolines; D000069476:Linagliptin