The persistent inhibitory properties of saxagliptin on renal dipeptidyl peptidase-4: Studies with HK-2 cells in vitro and normal rats in vivo
Saxagliptin, a potent and selective DPP-4 inhibitor, exhibits a slow dissociation from DPP-4. We investigated the sustained effects of saxagliptin on renal DPP-4 activity in a washout study using renal tubular (HK-2) cells, and in a pharmacodynamic study using normal rats. In HK-2 cells, the inhibit...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2017-11-01
|
| Series: | Journal of Pharmacological Sciences |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S134786131730172X |
| _version_ | 1818139323052064768 |
|---|---|
| author | Masako Uchii Mariko Sakai Yuhei Hotta Satoshi Saeki Naoya Kimoto Akinori Hamaguchi Tetsuya Kitayama Shunji Kunori |
| author_facet | Masako Uchii Mariko Sakai Yuhei Hotta Satoshi Saeki Naoya Kimoto Akinori Hamaguchi Tetsuya Kitayama Shunji Kunori |
| author_sort | Masako Uchii |
| collection | DOAJ |
| description | Saxagliptin, a potent and selective DPP-4 inhibitor, exhibits a slow dissociation from DPP-4. We investigated the sustained effects of saxagliptin on renal DPP-4 activity in a washout study using renal tubular (HK-2) cells, and in a pharmacodynamic study using normal rats. In HK-2 cells, the inhibitory potency of saxagliptin on DPP-4 activity persisted after washout, while that of sitagliptin was clearly reduced. In normal rats, a single treatment of saxagliptin or sitagliptin inhibited the plasma DPP-4 activity to similar levels. The inhibitory action of saxagliptin on the renal DPP-4 activity was retained, even when its inhibitory effect on the plasma DPP-4 activity disappeared. However, the inhibitory action of sitagliptin on the renal DPP-4 activity was abolished in correlation with the inhibition of the plasma DPP-4 activity. In situ staining showed that saxagliptin suppressed the DPP-4 activity in both glomerular and tubular cells and its inhibitory effects were significantly higher than those of sitagliptin. Saxagliptin exerted a sustained inhibitory effect on the renal DPP-4 activity in vitro and in vivo. The long binding action of saxagliptin in renal tubular cells might involve the sustained inhibition of renal DPP-4. |
| first_indexed | 2024-12-11T10:26:16Z |
| format | Article |
| id | doaj.art-4850ac17a9bd45a3be39b4af856c75ed |
| institution | Directory Open Access Journal |
| issn | 1347-8613 |
| language | English |
| last_indexed | 2024-12-11T10:26:16Z |
| publishDate | 2017-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Pharmacological Sciences |
| spelling | doaj.art-4850ac17a9bd45a3be39b4af856c75ed2022-12-22T01:11:09ZengElsevierJournal of Pharmacological Sciences1347-86132017-11-01135312613010.1016/j.jphs.2017.10.003The persistent inhibitory properties of saxagliptin on renal dipeptidyl peptidase-4: Studies with HK-2 cells in vitro and normal rats in vivoMasako Uchii0Mariko Sakai1Yuhei Hotta2Satoshi Saeki3Naoya Kimoto4Akinori Hamaguchi5Tetsuya Kitayama6Shunji Kunori7Nephrology Research Laboratories, Nephrology R&D Unit, R&D Division, Kyowa Hakko Kirin Co., Ltd., 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8731, JapanNephrology Research Laboratories, Nephrology R&D Unit, R&D Division, Kyowa Hakko Kirin Co., Ltd., 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8731, JapanNephrology Research Laboratories, Nephrology R&D Unit, R&D Division, Kyowa Hakko Kirin Co., Ltd., 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8731, JapanNephrology Research Laboratories, Nephrology R&D Unit, R&D Division, Kyowa Hakko Kirin Co., Ltd., 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8731, JapanTranslational Research Unit, R&D Division, Kyowa Hakko Kirin Co., Ltd., 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8731, JapanResearch Function Unit, R&D Division, Kyowa Hakko Kirin Co., Ltd., 3-6-6 Asahi-machi, Machida-shi, Tokyo 194-8533, JapanNephrology Research Laboratories, Nephrology R&D Unit, R&D Division, Kyowa Hakko Kirin Co., Ltd., 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8731, JapanNephrology Research Laboratories, Nephrology R&D Unit, R&D Division, Kyowa Hakko Kirin Co., Ltd., 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8731, JapanSaxagliptin, a potent and selective DPP-4 inhibitor, exhibits a slow dissociation from DPP-4. We investigated the sustained effects of saxagliptin on renal DPP-4 activity in a washout study using renal tubular (HK-2) cells, and in a pharmacodynamic study using normal rats. In HK-2 cells, the inhibitory potency of saxagliptin on DPP-4 activity persisted after washout, while that of sitagliptin was clearly reduced. In normal rats, a single treatment of saxagliptin or sitagliptin inhibited the plasma DPP-4 activity to similar levels. The inhibitory action of saxagliptin on the renal DPP-4 activity was retained, even when its inhibitory effect on the plasma DPP-4 activity disappeared. However, the inhibitory action of sitagliptin on the renal DPP-4 activity was abolished in correlation with the inhibition of the plasma DPP-4 activity. In situ staining showed that saxagliptin suppressed the DPP-4 activity in both glomerular and tubular cells and its inhibitory effects were significantly higher than those of sitagliptin. Saxagliptin exerted a sustained inhibitory effect on the renal DPP-4 activity in vitro and in vivo. The long binding action of saxagliptin in renal tubular cells might involve the sustained inhibition of renal DPP-4.http://www.sciencedirect.com/science/article/pii/S134786131730172XDipeptidyl peptidase-4 inhibitorSaxagliptinSitagliptinRenal dipeptidyl peptidase-4Renal tubular cells |
| spellingShingle | Masako Uchii Mariko Sakai Yuhei Hotta Satoshi Saeki Naoya Kimoto Akinori Hamaguchi Tetsuya Kitayama Shunji Kunori The persistent inhibitory properties of saxagliptin on renal dipeptidyl peptidase-4: Studies with HK-2 cells in vitro and normal rats in vivo Journal of Pharmacological Sciences Dipeptidyl peptidase-4 inhibitor Saxagliptin Sitagliptin Renal dipeptidyl peptidase-4 Renal tubular cells |
| title | The persistent inhibitory properties of saxagliptin on renal dipeptidyl peptidase-4: Studies with HK-2 cells in vitro and normal rats in vivo |
| title_full | The persistent inhibitory properties of saxagliptin on renal dipeptidyl peptidase-4: Studies with HK-2 cells in vitro and normal rats in vivo |
| title_fullStr | The persistent inhibitory properties of saxagliptin on renal dipeptidyl peptidase-4: Studies with HK-2 cells in vitro and normal rats in vivo |
| title_full_unstemmed | The persistent inhibitory properties of saxagliptin on renal dipeptidyl peptidase-4: Studies with HK-2 cells in vitro and normal rats in vivo |
| title_short | The persistent inhibitory properties of saxagliptin on renal dipeptidyl peptidase-4: Studies with HK-2 cells in vitro and normal rats in vivo |
| title_sort | persistent inhibitory properties of saxagliptin on renal dipeptidyl peptidase 4 studies with hk 2 cells in vitro and normal rats in vivo |
| topic | Dipeptidyl peptidase-4 inhibitor Saxagliptin Sitagliptin Renal dipeptidyl peptidase-4 Renal tubular cells |
| url | http://www.sciencedirect.com/science/article/pii/S134786131730172X |
| work_keys_str_mv | AT masakouchii thepersistentinhibitorypropertiesofsaxagliptinonrenaldipeptidylpeptidase4studieswithhk2cellsinvitroandnormalratsinvivo AT marikosakai thepersistentinhibitorypropertiesofsaxagliptinonrenaldipeptidylpeptidase4studieswithhk2cellsinvitroandnormalratsinvivo AT yuheihotta thepersistentinhibitorypropertiesofsaxagliptinonrenaldipeptidylpeptidase4studieswithhk2cellsinvitroandnormalratsinvivo AT satoshisaeki thepersistentinhibitorypropertiesofsaxagliptinonrenaldipeptidylpeptidase4studieswithhk2cellsinvitroandnormalratsinvivo AT naoyakimoto thepersistentinhibitorypropertiesofsaxagliptinonrenaldipeptidylpeptidase4studieswithhk2cellsinvitroandnormalratsinvivo AT akinorihamaguchi thepersistentinhibitorypropertiesofsaxagliptinonrenaldipeptidylpeptidase4studieswithhk2cellsinvitroandnormalratsinvivo AT tetsuyakitayama thepersistentinhibitorypropertiesofsaxagliptinonrenaldipeptidylpeptidase4studieswithhk2cellsinvitroandnormalratsinvivo AT shunjikunori thepersistentinhibitorypropertiesofsaxagliptinonrenaldipeptidylpeptidase4studieswithhk2cellsinvitroandnormalratsinvivo AT masakouchii persistentinhibitorypropertiesofsaxagliptinonrenaldipeptidylpeptidase4studieswithhk2cellsinvitroandnormalratsinvivo AT marikosakai persistentinhibitorypropertiesofsaxagliptinonrenaldipeptidylpeptidase4studieswithhk2cellsinvitroandnormalratsinvivo AT yuheihotta persistentinhibitorypropertiesofsaxagliptinonrenaldipeptidylpeptidase4studieswithhk2cellsinvitroandnormalratsinvivo AT satoshisaeki persistentinhibitorypropertiesofsaxagliptinonrenaldipeptidylpeptidase4studieswithhk2cellsinvitroandnormalratsinvivo AT naoyakimoto persistentinhibitorypropertiesofsaxagliptinonrenaldipeptidylpeptidase4studieswithhk2cellsinvitroandnormalratsinvivo AT akinorihamaguchi persistentinhibitorypropertiesofsaxagliptinonrenaldipeptidylpeptidase4studieswithhk2cellsinvitroandnormalratsinvivo AT tetsuyakitayama persistentinhibitorypropertiesofsaxagliptinonrenaldipeptidylpeptidase4studieswithhk2cellsinvitroandnormalratsinvivo AT shunjikunori persistentinhibitorypropertiesofsaxagliptinonrenaldipeptidylpeptidase4studieswithhk2cellsinvitroandnormalratsinvivo |