title: Hepatic Dipeptidyl Peptidase-4 Controls Pharmacokinetics of Vildagliptin In Vivo.
abstract: The main route of elimination of vildagliptin, which is an inhibitor of dipeptidyl peptidase-4 (DPP-4), in humans is cyano group hydrolysis to produce a carboxylic acid metabolite M20.7. Our in vitro study previously demonstrated that DPP-4 itself greatly contributed to the hydrolysis of vildagliptin in mouse, rat, and human livers. To investigate whether hepatic DPP-4 contributes to the hydrolysis of vildagliptin in vivo, in the present study, we conducted in vivo pharmacokinetics studies of vildagliptin in mice coadministered with vildagliptin and sitagliptin, which is another DPP-4 inhibitor, and also in streptozotocin (STZ)-induced diabetic mice. The area under the plasma concentration-time curve (AUC) value of M20.7 in mice coadministered with vildagliptin and sitagliptin was significantly lower than that in mice administered vildagliptin alone (P < 0.01). Although plasma DPP-4 expression level was increased 1.9-fold, hepatic DPP-4 activity was decreased in STZ-induced diabetic mice. The AUC values of M20.7 in STZ-induced diabetic mice were lower than those in control mice (P < 0.01). Additionally, the AUC values of M20.7 significantly positively correlated with hepatic DPP-4 activities in the individual mice (Rs = 0.943, P < 0.05). These findings indicated that DPP-4 greatly contributed to the hydrolysis of vildagliptin in vivo and that not plasma, but hepatic DPP-4 controlled pharmacokinetics of vildagliptin. Furthermore, enzyme assays of 23 individual human liver samples showed that there was a 3.6-fold interindividual variability in vildagliptin-hydrolyzing activities. Predetermination of the interindividual variability of hepatic vildagliptin-hydrolyzing activity might be useful for the prediction of blood vildagliptin concentrations in vivo.
authors.affiliation: Graduate School of Pharmaceutical Sciences (M.A.), Medicinal Research Laboratories (H.F.), Center for Clinical Pharmacy and Clinical Sciences (M.A., K.A.), Laboratory of Medicinal Chemistry (H.F.), and Department of Pharmaceutics (T.I., R.F.), School of Pharmacy, Kitasato University, Tokyo, Japan; Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan (T.F., M.N.).
authors.forename: Mitsutoshi
authors.initials: M
authors.lastname: Asakura
authors.affiliation: Graduate School of Pharmaceutical Sciences (M.A.), Medicinal Research Laboratories (H.F.), Center for Clinical Pharmacy and Clinical Sciences (M.A., K.A.), Laboratory of Medicinal Chemistry (H.F.), and Department of Pharmaceutics (T.I., R.F.), School of Pharmacy, Kitasato University, Tokyo, Japan; Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan (T.F., M.N.).
authors.forename: Tatsuki
authors.initials: T
authors.lastname: Fukami
authors.affiliation: Graduate School of Pharmaceutical Sciences (M.A.), Medicinal Research Laboratories (H.F.), Center for Clinical Pharmacy and Clinical Sciences (M.A., K.A.), Laboratory of Medicinal Chemistry (H.F.), and Department of Pharmaceutics (T.I., R.F.), School of Pharmacy, Kitasato University, Tokyo, Japan; Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan (T.F., M.N.).
authors.forename: Miki
authors.initials: M
authors.lastname: Nakajima
authors.affiliation: Graduate School of Pharmaceutical Sciences (M.A.), Medicinal Research Laboratories (H.F.), Center for Clinical Pharmacy and Clinical Sciences (M.A., K.A.), Laboratory of Medicinal Chemistry (H.F.), and Department of Pharmaceutics (T.I., R.F.), School of Pharmacy, Kitasato University, Tokyo, Japan; Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan (T.F., M.N.).
authors.forename: Hideaki
authors.initials: H
authors.lastname: Fujii
authors.affiliation: Graduate School of Pharmaceutical Sciences (M.A.), Medicinal Research Laboratories (H.F.), Center for Clinical Pharmacy and Clinical Sciences (M.A., K.A.), Laboratory of Medicinal Chemistry (H.F.), and Department of Pharmaceutics (T.I., R.F.), School of Pharmacy, Kitasato University, Tokyo, Japan; Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan (T.F., M.N.).
authors.forename: Koichiro
authors.initials: K
authors.lastname: Atsuda
authors.affiliation: Graduate School of Pharmaceutical Sciences (M.A.), Medicinal Research Laboratories (H.F.), Center for Clinical Pharmacy and Clinical Sciences (M.A., K.A.), Laboratory of Medicinal Chemistry (H.F.), and Department of Pharmaceutics (T.I., R.F.), School of Pharmacy, Kitasato University, Tokyo, Japan; Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan (T.F., M.N.).
authors.forename: Tomoo
authors.initials: T
authors.lastname: Itoh
authors.affiliation: Graduate School of Pharmaceutical Sciences (M.A.), Medicinal Research Laboratories (H.F.), Center for Clinical Pharmacy and Clinical Sciences (M.A., K.A.), Laboratory of Medicinal Chemistry (H.F.), and Department of Pharmaceutics (T.I., R.F.), School of Pharmacy, Kitasato University, Tokyo, Japan; Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan (T.F., M.N.) fujiwarar@pharm.kitasato-u.ac.jp.
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Fujiwara
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D018819:Dipeptidyl Peptidase 4 / Q000235:genetics / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D006868:Hydrolysis; D008099:Liver / Q000201:enzymology*; D008297:Male; D053858:Metabolic Networks and Pathways; D051379:Mice; D008810:Mice, Inbred C57BL; D009570:Nitriles / Q000097:blood / Q000493:pharmacokinetics*; D011759:Pyrrolidines / Q000097:blood / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D000077597:Vildagliptin
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D009570:Nitriles; D011759:Pyrrolidines; D018819:Dipeptidyl Peptidase 4; D000077597:Vildagliptin; D000218:Adamantane