ABSTRACT:The pharmacokinetics and metabolism of linagliptin (BI1356, 8-(3R-amino-piperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methylquinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione) were investigated in healthy volunteers. Type 2 diabetes mellitus (T2DM) accounts for 90 to 95% of all diabetes cases and its incidence is increasing (Wild et al., 2004). The high frequency of complications associated with the disease leads to a significant reduction in life expectancy. One relatively new therapeutic option is the inhibition of the enzyme dipeptidyl peptidase-4 (DPP-4), which is responsible for the rapid degradation of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide. After food intake, both hormones augment the action of insulin (Holst and Gromada, 2004;Mari et al., 2005;Drucker and Nauck, 2006;Drucker, 2007). The plasma half-life of GLP-1 is limited to a few minutes because of its rapid proteolytic degradation by DPP-4 (Graefe-Mody et al., 2009). Inhibitors of DPP-4 prolong the half-life of GLP-1 and glucose-dependent insulinotropic polypeptide, which leads to increases in glucose-dependent insulin secretion, inhibition of endogenous glucose production, decreased blood glucose, and the induction of feelings of satiety (Drucker, 2002;Nauck et al., 2003;Holst and Gromada, 2004).Linagliptin is a novel, orally active, highly specific, and potent inhibitor of DPP-4 that is currently in clinical development for the treatment of T2DM (Eckhardt et al., 2007;Fuchs et al., 2009b). Early clinical studies with linagliptin suggested a reduction in the glycated hemoglobin levels in patients with T2DM while maintaining a placebo-like safety and tolerability profile (Heise et al., 2009;Retlich et al., 2009). The pharmacokinetics of linagliptin were previously shown to be nonlinear due to target-mediated, concentrationdependent changes in binding to DPP-4 (Hüttner et al., 2008; Thomas et al., 2008a,b;Fuchs et al., 2009a;Heise et al., 2009).We report here a series of in vivo and in vitro studies performed to further establish the pharmacokinetics and metabolism of linagliptin in humans after intravenous and oral administration.Article, publication date, and citation information can be found at http://dmd.aspetjournals.org. doi:10.1124/dmd.109.031476.ABBREVIATIONS: T2DM, type 2 diabetes mellitus; DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; BI1355, 8-(3S-amino-piperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione; CD1790, 7-but-2-ynyl-8-(3S-hydroxy-piperidin-1-yl)-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione; CD1789, 7-but-2-ynyl-8-(3R-hydroxy-piperidin-1-yl)-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione; CD10604, 7-but-2-yn-1-yl-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]-8-(3-oxopiperidin-1-yl)-3, 7-dihydro-1H-purine-2,6-dione; LOQ, lower limit of quantification; LC-MS/MS, liquid chromatography-tandem mass spectrometry; HPLC, high-performance liquid chromat...