ArticlePharmaceutical research2023
Incorporating Uremic Solute-mediated Inhibition of OAT1/3 Improves PBPK Prediction of Tenofovir Renal and Systemic Disposition in Patients with Severe Kidney Disease.
Article in Pharmaceutical research, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
6 citing papers in PubMed, 8 citations in OpenAlex.
- Review
- Enhancing therapeutic strategies and drug development for patients with kidney disease.Expert opinion on drug safety · 2026Review
- Proximal tubule-on-chip as a model for predicting cation transport and drug transporter dynamics.Scientific reports · 2025Article
- High-performance PBPK model for predicting CYP3A4 induction-mediated drug interactions: a refined and validated approach.Frontiers in pharmacology · 2025Article
- Physiologically based pharmacokinetic modeling of small molecules: How much progress have we made?Drug metabolism and disposition: the biological fate of chemicals · 2025Review
- Application of Physiologically Based Pharmacokinetic Modeling in the Research of Anti-HIV Drugs.Current drug metabolism · 2025Review
Corrections and comments
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Authors and funding
10 authors at 1 institution in 1 country.
Funding
Abstract
backgroundDose modification of renally secreted drugs in patients with chronic kidney disease (CKD) has relied on serum creatinine concentration as a biomarker to estimate glomerular filtration (GFR) under the assumption that filtration and secretion decline in parallel. A discrepancy between actual renal clearance and predicted renal clearance based on GFR alone is observed in severe CKD patients with tenofovir, a compound secreted by renal OAT1/3. Uremic solutes that inhibit OAT1/3 may play a role in this divergence.
methodsTo examine the impact of transporter inhibition by uremic solutes on tenofovir renal clearance, we determined the inhibitory potential of uremic solutes hippuric acid, indoxyl sulfate, and p-cresol sulfate. The inhibition parameters (IC
resultsWithout the incorporation of uremic solute inhibition, the PBPK model failed to capture the observed data with an absolute average fold error (AAFE) > 2. However, when the inhibition of renal uptake transporters and uptake transporters in the slow distribution tissues were included, the AAFE value was within the pre-defined twofold model acceptance criterion, demonstrating successful model extrapolation to CKD patients.
conclusionA PBPK model that incorporates inhibition by uremic solutes has potential to better predict renal clearance and systemic disposition of secreted drugs in patients with CKD. Ongoing research is warranted to determine if the model can be expanded to include other OAT1/3 substrate drugs and to evaluate how these findings can be translated to clinical guidance for drug selection and dose optimization in patients with CKD.
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Registered trials
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