Abstract

Linagliptin is an orally active dipeptidyl peptidase-4 (DPP-4) inhibitor that is under development for the treatment of type 2 diabetes and shows dose-dependent pharmacokinetics in rats and humans. With microscopic autoradiography, the dose dependence of cellular distribution of [³H]linagliptin-related radioactivity was investigated in kidney at 3 h after intravenous injection of 7.4, 100, and 2000 μg/kg [³H]linagliptin. Furthermore, distribution of radioactivity in kidney, liver, and small intestine was investigated in relation to time (2 min, 3 h, and 192 h) after intravenous injection of 7.4 μg/kg [³H]linagliptin. The localization of radioactivity in the kidney at 3 h after administration of 7.4, 100, and 2000 μg/kg [³H]linagliptin changed with increasing dose from cortical glomeruli and parts of proximal tubule parts to parts of medullar proximal tubule. In addition, the compound distribution in the kidney shifted with time after administration of 7.4 μg/kg [³H]linagliptin from glomeruli (2 min) to the lower parts of proximal tubules (192 h). The radioactivity within proximal tubules was located primarily in the brush border. In the liver, the radioactivity persisted mainly around the portal triads and in the bile duct from 2 min to 192 h. In the small intestine, the radioactivity shifted from the lamina propria (2 min) to the surface of the villi and/or intestinal lumen (192 h). In conclusion, the cellular distribution pattern of [³H]linagliptin-related radioactivity reflected the known distribution of DPP-4. Together with the persistence of binding, this result supports the high relevance of DPP-4 binding of linagliptin for its pharmacokinetics and pharmacodynamics.