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Research ArticleArticle

Dipeptidyl Peptidase-4 Greatly Contributes to the Hydrolysis of Vildagliptin in Human Liver

Mitsutoshi Asakura, Hideaki Fujii, Koichiro Atsuda, Tomoo Itoh and Ryoichi Fujiwara
Drug Metabolism and Disposition April 2015, 43 (4) 477-484; DOI: https://doi.org/10.1124/dmd.114.062331
Mitsutoshi Asakura
Graduate School of Pharmaceutical Sciences (M.A.) and School of Pharmacy, Kitasato University, Tokyo, Japan (H.F., K.A., T.I., R.F.)
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Hideaki Fujii
Graduate School of Pharmaceutical Sciences (M.A.) and School of Pharmacy, Kitasato University, Tokyo, Japan (H.F., K.A., T.I., R.F.)
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Koichiro Atsuda
Graduate School of Pharmaceutical Sciences (M.A.) and School of Pharmacy, Kitasato University, Tokyo, Japan (H.F., K.A., T.I., R.F.)
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Tomoo Itoh
Graduate School of Pharmaceutical Sciences (M.A.) and School of Pharmacy, Kitasato University, Tokyo, Japan (H.F., K.A., T.I., R.F.)
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Ryoichi Fujiwara
Graduate School of Pharmaceutical Sciences (M.A.) and School of Pharmacy, Kitasato University, Tokyo, Japan (H.F., K.A., T.I., R.F.)
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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.

Footnotes

    • Received November 21, 2014.
    • Accepted January 15, 2015.
  • dx.doi.org/10.1124/dmd.114.062331.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 43 (4)
Drug Metabolism and Disposition
Vol. 43, Issue 4
1 Apr 2015
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Research ArticleArticle

DPP-4 Greatly Contributes to the Vildagliptin Hydrolysis

Mitsutoshi Asakura, Hideaki Fujii, Koichiro Atsuda, Tomoo Itoh and Ryoichi Fujiwara
Drug Metabolism and Disposition April 1, 2015, 43 (4) 477-484; DOI: https://doi.org/10.1124/dmd.114.062331

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Research ArticleArticle

DPP-4 Greatly Contributes to the Vildagliptin Hydrolysis

Mitsutoshi Asakura, Hideaki Fujii, Koichiro Atsuda, Tomoo Itoh and Ryoichi Fujiwara
Drug Metabolism and Disposition April 1, 2015, 43 (4) 477-484; DOI: https://doi.org/10.1124/dmd.114.062331
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