The Metabolism and Disposition of the Oral Dipeptidyl Peptidase-4 Inhibitor, Linagliptin, in Humans

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. The 10- and 5-mg (14)C-labeled drug was administered orally or intravenously, respectively. Fecal excretion was the dominant excretion pathway with 84.7% (p.o.) and 58.2% (i.v.) of the dose. Renal excretion accounted for 5.4% (p.o.) and 30.8% (i.v.) of the dose. Unchanged linagliptin was the most abundant radioactive species in all matrices investigated. The exposure (area under the curve 0-24 h) to the parent compound in plasma accounted for 191 nM.h (p.o.) and 356 nM.h (i.v.), respectively. The main metabolite 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 (CD1790) was observed with >10% of parent compound systemic exposure after oral administration. The metabolite was identified as S-3-hydroxypiperidinly derivative of linagliptin. Experiments that included stable-labeled isotope techniques indicated that CD1790 was formed by a two-step mechanism via the ketone 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 (CD10604). The initial ketone formation was CYP3A4-dependent and rate-limiting for the overall reaction to CD1790. Aldo-keto reductases with minor contribution of carbonyl reductases were involved in the subsequent stereoselective reduction of CD10604 to CD1790. The antipodes of linagliptin and CD1790 were not observed with adequate enantioselective liquid chromatography-tandem mass spectrometry methods. Other minor metabolites were identified by mass spectrometry and NMR investigations. However, it was concluded that the metabolites of linagliptin only play a minor role in the overall disposition and elimination of linagliptin.