scholarly journals Comparative Pharmacokinetics and Pharmacodynamics of a Novel Sodium-Glucose Cotransporter 2 Inhibitor, DWP16001, with Dapagliflozin and Ipragliflozin

Pharmaceutics ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 268
Author(s):  
Min-Koo Choi ◽  
So Jeong Nam ◽  
Hye-Young Ji ◽  
Mi Jie Park ◽  
Ji-Soo Choi ◽  
...  
Keyword(s):  
Organic Anion ◽  
Sglt2 Inhibitor ◽  
Sglt2 Inhibitors ◽  
Organic Anion Transporter ◽  
Plasma Exposure ◽  
Anion Transporter ◽  
Sodium Glucose Cotransporter ◽  
Glucose Reabsorption ◽  
Sglt2 Inhibition ◽  
Renal Tubular

Since sodium-glucose cotransporter 2 (SGLT2) inhibitors reduced blood glucose level by inhibiting renal tubular glucose reabsorption mediated by SGLT2, we aimed to investigate the pharmacokinetics and kidney distribution of DWP16001, a novel SGLT2 inhibitor, and to compare these properties with those of dapagliflozin and ipragliflozin, representative SGLT2 inhibitors. The plasma exposure of DWP16001 was comparable with that of ipragliflozin but higher than that of dapagliflozin. DWP16001 showed the highest kidney distribution among three SGLT2 inhibitors when expressed as an area under curve (AUC) ratio of kidney to plasma (85.0 ± 16.1 for DWP16001, 64.6 ± 31.8 for dapagliflozin and 38.4 ± 5.3 for ipragliflozin). The organic anion transporter-mediated kidney uptake of DWP16001 could be partly attributed to the highest kidney uptake. Additionally, DWP16001 had the lowest half-maximal inhibitory concentration (IC50) to SGLT2, a target transporter (0.8 ± 0.3 nM for DWP16001, 1.6 ± 0.3 nM for dapagliflozin, and 8.9 ± 1.7 nM for ipragliflozin). The inhibition mode of DWP16001 on SGLT2 was reversible and competitive, but the recovery of the SGLT2 inhibition after the removal of SGLT2 inhibitors in CHO cells overexpressing SGLT2 was retained with DWP16001, which is not the case with dapagliflozin and ipragliflozin. In conclusion, selective and competitive SGLT2 inhibition of DWP16001 could potentiate the efficacy of DWP16001 in coordination with the higher kidney distribution and retained SGLT2 inhibition of DWP16001 relative to dapagliflozin and ipragliflozin.

scholarly journals SGLT2 inhibition and kidney protection

2018 ◽  
Vol 132 (12) ◽  
pp. 1329-1339 ◽  
Author(s):  
Josselin Nespoux ◽  
Volker Vallon
Keyword(s):  
Kidney Injury ◽  
Sglt2 Inhibitors ◽  
Health Concern ◽  
Renal Outcome ◽  
Protective Effects ◽  
Drug Classes ◽  
Sodium Glucose Cotransporter ◽  
Glucose Reabsorption ◽  
Pressure Lowering ◽  
Sglt2 Inhibition

Type 2 diabetes mellitus (T2DM) is a growing public health concern worldwide. Numerous drug classes are available for treatment, however, their efficacy with regard to diabetes-induced renal and cardiovascular (CV) complications remains limited. Inhibitors of the sodium-glucose cotransporter 2 (SGLT2) are a new class of blood glucose lowering medications that block renal glucose reabsorption and have protective effects on the kidney and the heart. This review focusses on the effects of SGLT2 inhibitors on the kidney and renal outcome: it briefly outlines renal glucose handling in diabetes and its role in glomerular hyperfiltration and renal hypoxia; describes how SGLT2 inhibitors induce an early, reversible reduction in glomerular filtration rate (GFR) and preserve GFR in the long-term in patients with T2DM; discusses whether the enhanced active transport in the renal outer medulla (OM) in response to SGLT2 inhibition is friend or foe; proposes how the blood pressure lowering and heart failure protective effect of SGLT2 inhibitors can be preserved in chronic kidney disease (CKD) despite attenuated antihyperglycemic effects; and examines whether SGLT2 inhibition enhances the incidence or severity of acute kidney injury (AKI).

scholarly journals Impact of Lipopolysaccharide-Induced Inflammation on the Disposition of the Aminocephalosporin Cefadroxil

2013 ◽  
Vol 57 (12) ◽  
pp. 6171-6178 ◽  
Author(s):  
Yeamin Huh ◽  
Richard F. Keep ◽  
David E. Smith
Keyword(s):  
Choroid Plexus ◽  
Organic Anion ◽  
Tubular Secretion ◽  
Organic Anion Transporter ◽  
Peptide Transporter ◽  
Minor Role ◽  
Anion Transporter ◽  
Renal Tubular ◽  
A Minor ◽  
Lps Treatment

ABSTRACTThe purpose of this study was to determine if the disposition of cefadroxil, an α-amino-containing β-lactam antibiotic, changes during lipopolysaccharide (LPS)-induced acute inflammation. Six hours after LPS or saline treatment, mice received 1 nmol/g cefadroxil intravenously along with inulin for glomerular filtration rate (GFR) determination. Serial blood samples, along with tissue and urine samples, were collected at predetermined time points. In order to determine inflammation-induced changes in GFR, renal tubular secretion, and reabsorption, it was necessary to coadminister 70 mg/kg probenecid. Changes in the expression of the mRNA of transporters involved in cefadroxil disposition in the kidneys and choroid plexus were also investigated 6 h after LPS treatment. The results demonstrated marked increases in blood, cerebrospinal fluid, and tissue cefadroxil concentrations with LPS treatment. Tissue-to-blood concentration ratios were decreased by 4.6-fold in the choroid plexus and by 2.5-fold in the kidneys during LPS-induced inflammation. Renal, but not choroid plexus, mRNA expression of peptide transporter 2, organic-anion transporter 1 (OAT1), OAT3, and multidrug resistance-associated protein 4 was mildly reduced in LPS-treated mice. The renal clearance of cefadroxil was substantially decreased by LPS treatment (3-fold). GFR was also reduced by 3-fold in LPS-treated mice, but no significant differences in the fractional reabsorption of cefadroxil and renal secretion once normalized by GFR were observed. These findings demonstrated that LPS-induced inflammation has a dramatic effect on the renal excretion of cefadroxil. It appears that changes in transporter expression played a minor role during LPS treatment but that renal dysfunction, associated with GFR reduction, was responsible for the substantial increase in plasma cefadroxil concentration-time profiles.

scholarly journals Organic anion transporter OAT3 enhances the glucosuric effect of the SGLT2 inhibitor empagliflozin

2018 ◽  
Vol 315 (2) ◽  
pp. F386-F394 ◽  
Author(s):  
Yiling Fu ◽  
Davorka Breljak ◽  
Akira Onishi ◽  
Falk Batz ◽  
Rohit Patel ◽  
...  
Keyword(s):  
Proximal Tubule ◽  
Glomerular Filtration ◽  
Organic Anion ◽  
Sglt2 Inhibitor ◽  
Tubular Secretion ◽  
Organic Anion Transporter ◽  
Renal Tubules ◽  
Anion Transporter ◽  
Glucose Excretion ◽  
Early Proximal Tubule

The sodium-glucose cotransporter SGLT2 inhibitor empagliflozin (plasma protein binding ~88%) may reach its target in the brush border of the early proximal tubule by glomerular filtration and tubular secretion. Here we determined whether empagliflozin is secreted by renal tubules in mice and whether genetic knockout of the basolateral organic anion transporter 3 ( Oat3−/−) affects its tubular secretion or glucosuric effect. Renal clearance studies in wild-type (WT) mice showed that tubular secretion accounted for 50–70% of empagliflozin urinary excretion. Immunostaining indicated that SGLT2 and OAT3 localization partially overlapped in proximal tubule S1 and S2 segments. Glucosuria in metabolic cage studies was reduced in Oat3−/− vs. WT mice for acute empagliflozin doses of 1, 3, and 10 mg/kg, whereas 30 mg/kg induced similar maximal glucosuria in both genotypes. Chronic application of empagliflozin (~25 mg·kg−1 ·day−1) in Oat3−/− mice was associated with lower urinary glucose-to-creatinine ratios despite maintaining slightly higher blood glucose levels than WT. On a whole kidney level, renal secretion of empagliflozin was largely unchanged in Oat3−/− mice. However, the absence of OAT3 attenuated the influence of empagliflozin on fractional glucose excretion; higher levels of plasma or filtered empagliflozin were needed to induce similar increases in fractional renal glucose excretion. We conclude that empagliflozin is excreted into the urine to similar extent by glomerular filtration and tubular secretion. The latter can occur largely independent of OAT3. However, OAT3 increases the glucosuric effect of empagliflozin, which may relate to the partial overlap of its localization with SGLT2 and thus OAT3-mediated tubular secretion of empagliflozin in the early proximal tubule.

scholarly journals Sodium-glucose cotransporter-2 inhibitors: Understanding the mechanisms for therapeutic promise and persisting risks

2020 ◽  
Vol 295 (42) ◽  
pp. 14379-14390
Author(s):  
Rachel J. Perry ◽  
Gerald I. Shulman
Keyword(s):  
Diabetes Management ◽  
Sglt2 Inhibitor ◽  
Healthy Person ◽  
The United States ◽  
Sglt2 Inhibitors ◽  
Beneficial Effects ◽  
Sodium Glucose Cotransporter ◽  
Glucose Reabsorption ◽  
Almost All ◽  
The Impact

In a healthy person, the kidney filters nearly 200 g of glucose per day, almost all of which is reabsorbed. The primary transporter responsible for renal glucose reabsorption is sodium-glucose cotransporter-2 (SGLT2). Based on the impact of SGLT2 to prevent renal glucose wasting, SGLT2 inhibitors have been developed to treat diabetes and are the newest class of glucose-lowering agents approved in the United States. By inhibiting glucose reabsorption in the proximal tubule, these agents promote glycosuria, thereby reducing blood glucose concentrations and often resulting in modest weight loss. Recent work in humans and rodents has demonstrated that the clinical utility of these agents may not be limited to diabetes management: SGLT2 inhibitors have also shown therapeutic promise in improving outcomes in heart failure, atrial fibrillation, and, in preclinical studies, certain cancers. Unfortunately, these benefits are not without risk: SGLT2 inhibitors predispose to euglycemic ketoacidosis in those with type 2 diabetes and, largely for this reason, are not approved to treat type 1 diabetes. The mechanism for each of the beneficial and harmful effects of SGLT2 inhibitors—with the exception of their effect to lower plasma glucose concentrations—is an area of active investigation. In this review, we discuss the mechanisms by which these drugs cause euglycemic ketoacidosis and hyperglucagonemia and stimulate hepatic gluconeogenesis as well as their beneficial effects in cardiovascular disease and cancer. In so doing, we aim to highlight the crucial role for selecting patients for SGLT2 inhibitor therapy and highlight several crucial questions that remain unanswered.

Selective SGLT2 inhibition by tofogliflozin reduces renal glucose reabsorption under hyperglycemic but not under hypo- or euglycemic conditions in rats

2013 ◽  
Vol 304 (4) ◽  
pp. E414-E423 ◽  
Author(s):  
Takumi Nagata ◽  
Masanori Fukazawa ◽  
Kiyofumi Honda ◽  
Tatsuo Yata ◽  
Mio Kawai ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
Sglt2 Inhibitor ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Sodium Glucose Cotransporter ◽  
Glucose Reabsorption ◽  
Urinary Glucose ◽  
Sglt2 Inhibition ◽  
Renal Glucose Reabsorption

To understand the risk of hypoglycemia associated with urinary glucose excretion (UGE) induced by sodium-glucose cotransporter (SGLT) inhibitors, it is necessary to know the relationship between the ratio of contribution of SGLT2 vs. SGLT1 to renal glucose reabsorption (RGR) and the glycemic levels in vivo. To examine the contributions of SGLT2 and SGLT1 in normal rats, we compared the RGR inhibition by tofogliflozin, a highly specific SGLT2 inhibitor, and phlorizin, an SGLT1 and SGLT2 (SGLT1/2) inhibitor, at plasma concentrations sufficient to completely inhibit rat SGLT2 (rSGLT2) while inhibiting rSGLT1 to different degrees. Under hyperglycemic conditions by glucose titration, tofogliflozin and phlorizin achieved ≥50% inhibition of RGR. Under hypoglycemic conditions by hyperinsulinemic clamp, RGR was reduced by 20–50% with phlorizin and by 1–5% with tofogliflozin, suggesting the smaller contribution of rSGLT2 to RGR under hypoglycemic conditions than under hyperglycemic conditions. Next, to evaluate the hypoglycemic potentials of SGLT1/2 inhibition, we measured the plasma glucose (PG) and endogenous glucose production (EGP) simultaneously after UGE induction by SGLT inhibitors. Tofogliflozin (400 ng/ml) induced UGE of about 2 mg·kg−1·min−1 and increased EGP by 1–2 mg·kg−1·min−1, resulting in PG in the normal range. Phlorizin (1,333 ng/ml) induced UGE of about 6 mg·kg−1·min−1 and increased EGP by about 4 mg·kg−1·min−1; this was more than with tofogliflozin, but the minimum PG was lower. These results suggest that the contribution of SGLT1 to RGR is greater under lower glycemic conditions than under hyperglycemic conditions and that SGLT2-selective inhibitors pose a lower risk of hypoglycemia than SGLT1/2 inhibitors.

Characterization of hepatobiliary organic anion transporter regulation in the Zucker rat

2004 ◽  
Vol 42 (08) ◽  
Author(s):  
A Geier ◽  
CG Dietrich ◽  
C Gartung ◽  
F Lammert ◽  
HE Wasmuth ◽  
...  
Keyword(s):  
Organic Anion ◽  
Organic Anion Transporter ◽  
Zucker Rat ◽  
Anion Transporter
Sign in / Sign up

Export Citation Format

Share Document