title: Dipeptidyl peptidase-4 greatly contributes to the hydrolysis of vildagliptin in human liver.
abstract: The major metabolic pathway of vildagliptin in mice, rats, dogs, and humans is hydrolysis at the cyano group to produce a carboxylic acid metabolite M20.7 (LAY151), whereas the major metabolic enzyme of vildagliptin has not been identified. In the present study, we determined the contribution rate of dipeptidyl peptidase-4 (DPP-4) to the hydrolysis of vildagliptin in the liver. We performed hydrolysis assay of the cyano group of vildagliptin using mouse, rat, and human liver samples. Additionally, DPP-4 activities in each liver sample were assessed by DPP-4 activity assay using the synthetic substrate H-glycyl-prolyl-7-amino-4-methylcoumarin (Gly-Pro-AMC). M20.7 formation rates in liver microsomes were higher than those in liver cytosol. M20.7 formation rate was significantly positively correlated with the DPP-4 activity using Gly-Pro-AMC in liver samples (r = 0.917, P < 0.01). The formation of M20.7 in mouse, rat, and human liver S9 fraction was inhibited by sitagliptin, a selective DPP-4 inhibitor. These findings indicate that DPP-4 is greatly involved in vildagliptin hydrolysis in the liver. Additionally, we established stable single expression systems of human DPP-4 and its R623Q mutant, which is the nonsynonymous single-nucleotide polymorphism of human DPP-4, in human embryonic kidney 293 (HEK293) cells to investigate the effect of R623Q mutant on vildagliptin-hydrolyzing activity. M20.7 formation rate in HEK293 cells expressing human DPP-4 was significantly higher than that in control HEK293 cells. Interestingly, R623Q mutation resulted in a decrease of the vildagliptin-hydrolyzing activity. Our findings might be useful for the prediction of interindividual variability in vildagliptin pharmacokinetics.
authors.affiliation: Graduate School of Pharmaceutical Sciences (M.A.) and School of Pharmacy, Kitasato University, Tokyo, Japan (H.F., K.A., T.I., R.F.).
authors.forename: Mitsutoshi
authors.initials: M
authors.lastname: Asakura
authors.affiliation: Graduate School of Pharmaceutical Sciences (M.A.) and School of Pharmacy, Kitasato University, Tokyo, Japan (H.F., K.A., T.I., R.F.).
authors.forename: Hideaki
authors.initials: H
authors.lastname: Fujii
authors.affiliation: Graduate School of Pharmaceutical Sciences (M.A.) and School of Pharmacy, Kitasato University, Tokyo, Japan (H.F., K.A., T.I., R.F.).
authors.forename: Koichiro
authors.initials: K
authors.lastname: Atsuda
authors.affiliation: Graduate School of Pharmaceutical Sciences (M.A.) and School of Pharmacy, Kitasato University, Tokyo, Japan (H.F., K.A., T.I., R.F.).
authors.forename: Tomoo
authors.initials: T
authors.lastname: Itoh
authors.affiliation: Graduate School of Pharmaceutical Sciences (M.A.) and School of Pharmacy, Kitasato University, Tokyo, Japan (H.F., K.A., T.I., R.F.) fujiwarar@pharm.kitasato-u.ac.jp.
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Fujiwara
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001711:Biotransformation; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000235:genetics / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D006868:Hydrolysis; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D009570:Nitriles / Q000493:pharmacokinetics* / Q000494:pharmacology; D011759:Pyrrolidines / Q000493:pharmacokinetics* / Q000494:pharmacology; D011916:Rats, Inbred F344; D013045:Species Specificity; D014162:Transfection; D000077597:Vildagliptin
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D009570:Nitriles; D011759:Pyrrolidines; D018819:Dipeptidyl Peptidase 4; D000077597:Vildagliptin; D000218:Adamantane