Abstract:
: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.
journal_name
J Pharmacol Scijournal_title
Journal of pharmacological sciencesauthors
Uchii M,Sakai M,Hotta Y,Saeki S,Kimoto N,Hamaguchi A,Kitayama T,Kunori Sdoi
10.1016/j.jphs.2017.10.003subject
Has Abstractpub_date
2017-11-01 00:00:00pages
126-130issue
3eissn
1347-8613issn
1347-8648pii
S1347-8613(17)30172-Xjournal_volume
135pub_type
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