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Target Concepts:
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Query: UNIPROT:Q08357 (
SLC20A2
)
172
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Phosphate is absorbed in the small intestine by a minimum of 2 distinct mechanisms: paracellular phosphate transport which is dependent on passive diffusion, and active transport which occurs through the sodium-dependent phosphate cotransporters. Despite evidence emerging for other ions, regulation of the phosphate-specific paracellular pathways remains largely unexplored. In contrast, there is a growing body of evidence that active transport through the sodium-dependent phosphate cotransporter, Npt2b, is highly regulated by a diverse set of hormones and dietary conditions. Furthermore, conditional knockout of Npt2b suggests that it plays an important role in maintenance of phosphate homeostasis by coordinating intestinal phosphate absorption with renal phosphate reabsorption. The knockout mouse also suggests that Npt2b is responsible for the majority of sodium-dependent phosphate uptake. The type-III sodium-dependent phosphate transporters, Pit1 and
Pit2
, contribute to a minor role in total phosphate uptake. Despite coexpression along the apical membrane, differential responses of Pit1 and Npt2b regulation to chronic versus dietary changes illustrates another layer of phosphate transport control. Finally, a major problem in patients with CKD is management of
hyperphosphatemia
. The present evidence suggests that targeting key regulatory pathways of intestinal phosphate transport may provide novel therapeutic approaches for patients with CKD.
...
PMID:Intestinal phosphate transport. 2140 92
A treatment for
hyperphosphatemia
would be expected to reduce mortality rates for CKD and dialysis patients. Although rodent studies have suggested sodium-dependent phosphate transporter type IIb (NaPi-IIb) as a potential target for
hyperphosphatemia
, NaPi-IIb selective inhibitors failed to achieve efficacy in human clinical trials. In this study, we analyzed phosphate metabolism in rats, dogs, and monkeys to confirm the species differences. Factors related to phosphate metabolism were measured and intestinal phosphate absorption rate was calculated from fecal excretion in each species. Phosphate uptake by intestinal brush border membrane vesicles (BBMV) and the mRNA expression of NaPi-IIb, PiT-1, and
PiT-2
were analyzed. In addition, alkaline phosphatase (ALP) activity was evaluated. The intestinal phosphate absorption rate, including phosphate uptake by BBMV and NaPi-IIb expression, was the highest in dogs. Notably, urinary phosphate excretion was the lowest in monkeys, and their intestinal phosphate absorption rate was by far the lowest. Dogs and rats showed positive correlations between V
max
/K
m
of phosphate uptake in BBMV and NaPi-IIb expression. Although phosphate uptake was observed in the BBMV of monkeys, NaPi-IIb expression was not detected and ALP activity was low. This study revealed significant species differences in intestinal phosphate absorption. NaPi-IIb contributes to intestinal phosphate uptake in rats and dogs. However, in monkeys, phosphate is poorly absorbed due to the slight degradation of organic phosphate in the intestine.
...
PMID:Significant Species Differences in Intestinal Phosphate Absorption between Dogs, Rats, and Monkeys. 3211 55
Chronic kidney disease is characterized as impaired renal function along with the imbalance and dysregulation of mineral metabolism; recognized as chronic kidney disease-mineral and bone disorder.
Hyperphosphatemia
, characterized by altered phosphate homeostasis along with elevated fibroblast growth factor-23 and intact parathyroid hormone, is such an alteration of mineral metabolism. We discovered a novel inhibitor, EOS789, that interacts with several sodium-dependent phosphate transporters (NaPi-IIb, PiT-1, and
PiT-2
) known to contribute to intestinal phosphate absorption. This inhibitor dose-dependently increased the fecal phosphorus excretion rate and inversely decreased the urinary phosphorus excretion rate in normal rats, suggesting inhibition of intestinal phosphorus absorption. In rats with adenine-induced
hyperphosphatemia
, EOS789 markedly decreased the serum phosphate, fibroblast growth factor-23, and intact parathyroid hormone below values found in normal control rats. Notably, this pan-phosphate transporter inhibitor exhibited a more potent effect on serum phosphate than a NaPi-IIb-selective inhibitor in rats with
hyperphosphatemia
indicating that PiT-1 and
PiT-2
play important roles in intestinal phosphate absorption. Moreover, in a long-term study, EOS789 sustained the suppression of serum phosphorus in parallel with fibroblast growth factor-23 and intact parathyroid hormone and ameliorated ectopic calcification of the thoracic aorta. Additionally, EOS789 treatment also ameliorated kidney deterioration in rats with progressive kidney injury, probably due to the strict phosphate control. Thus, EOS789 has potent efficacy against
hyperphosphatemia
and its complications and could provide a significant benefit to patients who are ineffectively treated with phosphate binders.
...
PMID:EOS789, a novel pan-phosphate transporter inhibitor, is effective for the treatment of chronic kidney disease-mineral bone disorder. 3262 80
The treatment of
hyperphosphatemia
remains challenging in patients receiving hemodialysis. This Phase 1b study assessed safety and efficacy of EOS789, a novel pan-inhibitor of phosphate transport (NaPi-2b, PiT-1,
PiT-2
) on intestinal phosphate absorption in patients receiving intermittent hemodialysis therapy. Two cross-over, randomized order studies of identical design (ten patients each) compared daily EOS789 50 mg to placebo with meals and daily EOS789 100 mg vs EOS789 100 mg plus 1600 mg sevelamer with meals. Patients ate a controlled diet of 900 mg phosphate daily for two weeks and began EOS789 on day four. On day ten, a phosphate absorption testing protocol was performed during the intradialytic period. Intestinal fractional phosphate absorption was determined by kinetic modeling of serum data following oral and intravenous doses of
33
Phosphate (
33
P). The results demonstrated no study drug related serious adverse events. Fractional phosphate absorption was 0.53 (95% confidence interval: 0.39,0.67) for placebo vs. 0.49 (0.35,0.63) for 50 mg EOS789; and 0.40 (0.29,0.50) for 100 mg EOS789 vs. 0.36 (0.26,0.47) for 100 mg EOS789 plus 1600 mg sevelamer (all not significantly different). The fractional phosphate absorption trended lower in six patients who completed both studies with EOS789 100 mg compared with placebo. Thus, in this Phase 1b study, EOS789 was safe and well tolerated. Importantly, the use of
33
P as a sensitive and direct measure of intestinal phosphate absorption allows specific testing of drug efficacy. The effectiveness of EOS789 needs to be evaluated in future Phase 2 and Phase 3 studies.
...
PMID:EOS789, a broad-spectrum inhibitor of phosphate transport, is safe with an indication of efficacy in a Phase 1b randomized cross-over trial in hemodialysis patients. 3313 40
