Identification and Quantitative Assessment of Uremic Solutes as Inhibitors of Renal Organic Anion Transporters, OAT1 and OAT3

Hsueh, Chia‐Hsiang; Yoshida, Kenta; Zhao, Ping; Meyer, Timothy W.; Zhang, Lei; Huang, Shiew‐Mei; Giacomini, Kathleen M.

doi:10.1021/acs.molpharmaceut.6b00332

Cited by 81 publications

(114 citation statements)

References 72 publications

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“…In this study, levels of uremic toxins and uremic solutes were analyzed from the plasma of the Oat1KO and Oat3KO , as well as from Oat3KO s treated with probenecid (“chemical double knockouts”). Among the more than 600 metabolites examined, ~90 of them are water-soluble or protein-bound uremic toxins/retentions solutes identified by a number of groups (Supplemental Table S1) 1, 2, 25–29 . Partial least squares discriminant analysis of these uremic toxins/retention solutes revealed separation of both Oat1KO and Oat3KO groups from their wildtype controls (Supplemental Figure 1).…”

Section: Resultsmentioning

confidence: 99%

Key Role for the Organic Anion Transporters, OAT1 and OAT3, in the in vivo Handling of Uremic Toxins and Solutes

Bush

Nigám

2017

Sci Rep

164

176

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In vitro data indicates that the kidney proximal tubule (PT) transporters of uremic toxins and solutes (e.g., indoxyl sulfate, p-cresol sulfate, kynurenine, creatinine, urate) include two “drug” transporters of the organic anion transporter (OAT) family: OAT1 (SLC22A6, originally NKT) and OAT3 (SLC22A8). Here, we have examined new and prior metabolomics data from the Oat1KO and Oat3KO, as well as newly obtained metabolomics data from a “chemical double” knockout (Oat3KO plus probenecid). This gives a picture of the in vivo roles of OAT1 and OAT3 in the regulation of the uremic solutes and supports the centrality of these “drug” transporters in independently and synergistically regulating uremic metabolism. We demonstrate a key in vivo role for OAT1 and/or OAT3 in the handling of over 35 uremic toxins and solutes, including those derived from the gut microbiome (e.g., CMPF, phenylsulfate, indole-3-acetic acid). Although it is not clear whether trimethylamine-N-oxide (TMAO) is directly transported, the Oat3KO had elevated plasma levels of TMAO, which is associated with cardiovascular morbidity in chronic kidney disease (CKD). As described in the Remote Sensing and Signaling (RSS) Hypothesis, many of these molecules are involved in interorgan and interorganismal communication, suggesting that uremia is, at least in part, a disorder of RSS.

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Section: Resultsmentioning

confidence: 99%

Key Role for the Organic Anion Transporters, OAT1 and OAT3, in the in vivo Handling of Uremic Toxins and Solutes

Bush

Nigám

2017

Sci Rep

164

176

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“…A previous study simulated the impact of reduced proximal tubule cellularity on plasma drug concentrations and CL R (Hsu et al, 2014). However, experimental data on proximal tubule cellularity for healthy and diseased kidneys are unlikely to become available soon, whereas information on inhibitory potential of uremic solutes on renal transporters and transporter abundances are now emerging (Fallon et al, 2016; Hsueh et al, 2016; Prasad et al, 2016). In the current study, after evaluation in the healthy population, a PBPK kidney model for digoxin was applied to investigate the simulated effect of renal impairment on plasma concentrations, CL R and proximal tubule concentrations.…”

Section: Discussionmentioning

confidence: 99%

“…Various underlying physiological changes have been proposed to cause reduced tubular secretion in renal impairment, including transporter inhibition by uremic solutes, loss of proximal tubule cells, and decreases in transporter expression levels (Naud et al, 2011; Hsueh et al, 2016). Therefore, to mimic renal impairment, changes to transporter abundance (OATP4C1 and P-gp) per million proximal tubule cells and proximal tubule cellularity parameters of the model were considered in the current study.…”

Section: Discussionmentioning

confidence: 99%

Delineating the Role of Various Factors in Renal Disposition of Digoxin through Application of Physiologically Based Kidney Model to Renal Impairment Populations

Scotcher

Jones

Galetin

et al. 2017

J Pharmacol Exp Ther

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Development of submodels of organs within physiologically-based pharmacokinetic (PBPK) principles and beyond simple perfusion limitations may be challenging because of underdeveloped in vitro-in vivo extrapolation approaches or lack of suitable clinical data for model refinement. However, advantage of such models in predicting clinical observations in divergent patient groups is now commonly acknowledged. Mechanistic understanding of altered renal secretion in renal impairment is one area that may benefit from such models, despite knowledge gaps in renal pathophysiology. In the current study, a PBPK kidney model was developed for digoxin, accounting for the roles of organic anion transporting peptide 4C1 (OATP4C1) and P-glycoprotein (P-gp) in its tubular secretion, with the aim to investigate the impact of age and renal impairment (moderate to severe) on renal drug disposition. Initial PBPK simulations based on changes in glomerular filtration rate (GFR) underestimated the observed reduction in digoxin renal excretion clearance (CLR) in subjects with moderately impaired renal function relative to healthy. Reduction in either proximal tubule cell number or the OATP4C1 abundance in the mechanistic kidney model successfully predicted 59% decrease in digoxin CLR, in particular when these changes were proportional to reduction in GFR. In contrast, predicted proximal tubule concentration of digoxin was only sensitive to changes in the transporter expression/ million proximal tubule cells. Based on the mechanistic modeling, reduced proximal tubule cellularity and OATP4C1 abundance, and inhibition of OATP4C1-mediated transport, are proposed as possible causes of reduced digoxin renal secretion in renally impaired patients.

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“…Indeed, levels of indoxyl sulfate were higher in the brain and plasma of patients with renal insufficiency compared to control subjects [62]. Increased levels of indoxyl sulfate in the plasma could also impair the ability of the brain transporters to remove other solutes, as inhibition of related transporters by indoxyl sulfate in kidney and liver cells has been demonstrated [17,63,64,65]. …”

Section: Evidence For Toxicitymentioning

confidence: 99%

Indoxyl Sulfate—Review of Toxicity and Therapeutic Strategies

Leong

Sirich

2016

Toxins

198

178

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Indoxyl sulfate is an extensively studied uremic solute. It is a small molecule that is more than 90% bound to plasma proteins. Indoxyl sulfate is derived from the breakdown of tryptophan by colon microbes. The kidneys achieve high clearances of indoxyl sulfate by tubular secretion, a function not replicated by hemodialysis. Clearance by hemodialysis is limited by protein binding since only the free, unbound solute can diffuse across the membrane. Since the dialytic clearance is much lower than the kidney clearance, indoxyl sulfate accumulates to relatively high plasma levels in hemodialysis patients. Indoxyl sulfate has been most frequently implicated as a contributor to renal disease progression and vascular disease. Studies have suggested that indoxyl sulfate also has adverse effects on bones and the central nervous system. The majority of studies have assessed toxicity in cultured cells and animal models. The toxicity in humans has not yet been proven, as most data have been from association studies. Such toxicity data, albeit inconclusive, have prompted efforts to lower the plasma levels of indoxyl sulfate through dialytic and non-dialytic means. The largest randomized trial showed no benefit in renal disease progression with AST-120. No trials have yet tested cardiovascular or mortality benefit. Without such trials, the toxicity of indoxyl sulfate cannot be firmly established.

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Identification and Quantitative Assessment of Uremic Solutes as Inhibitors of Renal Organic Anion Transporters, OAT1 and OAT3

Cited by 81 publications

References 72 publications

Key Role for the Organic Anion Transporters, OAT1 and OAT3, in the in vivo Handling of Uremic Toxins and Solutes

Key Role for the Organic Anion Transporters, OAT1 and OAT3, in the in vivo Handling of Uremic Toxins and Solutes

Delineating the Role of Various Factors in Renal Disposition of Digoxin through Application of Physiologically Based Kidney Model to Renal Impairment Populations

Indoxyl Sulfate—Review of Toxicity and Therapeutic Strategies

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