ArticleEuropean journal of clinical pharmacology2014
Inhibition of human drug-metabolising cytochrome P450 and UDP-glucuronosyltransferase enzyme activities in vitro by uremic toxins.
Article in European journal of clinical pharmacology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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Who cites it
41 citing papers in PubMed, 74 citations in OpenAlex.
- Impact of CYP2C19 polymorphism in prognosis of minor stroke or TIA patients with declined eGFR on dual antiplatelet therapy: CHANCE substudy.The pharmacogenomics journal · 2018Trial
- Impacts of Uremic Toxins on the Population Pharmacokinetics of Total Mycophenolic Acid and its Glucuronide Metabolite in Adult Kidney Transplant Recipients.Clinical pharmacokinetics · 2026Observational
- Effects of Renal and Hepatic Impairment on the Pharmacokinetics of Zilurgisertib.British journal of clinical pharmacology · 2026Article
- Article
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- Integrated Physiologically-Based Pharmacokinetic Model with a Quantitative Systems Pharmacology and Toxicology Model for Statins in Disease Population. Part 1: Model Development and Validation.The AAPS journal · 2025Article
- The impact of progressive chronic kidney disease on hepatic drug metabolism.Drug metabolism and disposition: the biological fate of chemicals · 2025Article
- Population pharmacokinetic and pharmacodynamic model of evogliptin: Severe uremia increases the bioavailability of evogliptin.CPT: pharmacometrics & systems pharmacology · 2025Article
- The evolving understanding of systemic mechanisms in organ-specific IgA nephropathy: a focus on gut-kidney crosstalk.Theranostics · 2025Review
- Prospective Trial on the Pharmacokinetics of Clopidogrel in Hemodialysis Patients.Kidney international reports · 2024Article
- Evaluation of Renal Impairment Influence on Metabolic Drug Clearance using a Modelling Approach.Clinical pharmacokinetics · 2023Article
- The Impact of Suboptimal 25-Hydroxyvitamin D Levels and Cholecalciferol Replacement on the Pharmacokinetics of Oral Midazolam in Control Subjects and Patients With Chronic Kidney Disease.Journal of clinical pharmacology · 2022Article
- Drug-Drug Interactions in People Living With HIV at Risk of Hepatic and Renal Impairment: Current Status and Future Perspectives.Journal of clinical pharmacology · 2022Review
- Microbiota in health and diseases.Signal transduction and targeted therapy · 2022Review
- Small phenolic and indolic gut-dependent molecules in the primate central nervous system: levels vs. bioactivity.Metabolomics : Official journal of the Metabolomic Society · 2022Article
- Pretherapeutic screening for Dihydropyrimidine deshydrogenase deficiency in measuring uracilemia in dialysis patients leads to a high rate of falsely positive results.Cancer chemotherapy and pharmacology · 2021Article
- Sources of Interindividual Variability.Methods in molecular biology (Clifton, N.J.) · 2021Article
- Comparisons of Four Protein-Binding Models Characterizing the Pharmacokinetics of Unbound Phenytoin in Adult Patients Using Non-Linear Mixed-Effects Modeling.Drugs in R&D · 2020Article
- End-stage renal disease reduces the expression of drug-metabolizing cytochrome P450s.Pharmacological reports : PR · 2020Article
- Testing the Pharmacokinetic Interactions of 24 Colonic Flavonoid Metabolites with Human Serum Albumin and Cytochrome P450 Enzymes.Biomolecules · 2020Article
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
objectiveTo investigate the potential inhibitory effects of uremic toxins on the major human hepatic drug-metabolising cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) enzymes in vitro.
methodsBenzyl alcohol, p-cresol, indoxyl sulfate, hippuric acid and a combination of the four uremic toxins were co-incubated with human liver microsomes and selective probe substrates for the major human drug-metabolising CYP and UGT enzymes. The percentage of enzyme inhibition was calculated by measuring the rates of probe metabolite formation in the absence and presence of the uremic toxins. Kinetics studies were conducted to evaluate the K i values and mechanism(s) of the inhibition of CYP2E1, CYP3A4, UGT1A1 and UGT1A9 by p-cresol.
resultsThe individual uremic toxins inhibited CYP and UGT enzymes to a variable extent. p-Cresol was the most potent individual inhibitor, producing >50% inhibition of CYP2E1, CYP3A4, UGT1A1, UGT1A9 and UGT2B7 at a concentration of 100 μM. The greatest inhibition was observed with UGT1A9. p-Cresol was shown to be an uncompetitive inhibitor of UGT1A9, with unbound K i values of 9.1 and 2.5 μM in the absence and presence of bovine serum albumin (BSA), respectively. K i values for p-cresol inhibition of human liver microsomal CYP2E1, CYP3A4 and UGT1A1 ranged from 43 to 89 μM. A combination of the four uremic toxins produced >50% decreases in the activities of CYP1A2, CYP2C9, CYP2E1, CYP3A4, UGT1A1, UGT1A9 and UGT2B7.
conclusionsUremic toxins may contribute to decreases in drug hepatic clearance in individuals with kidney disease by inhibition of hepatic drug-metabolising enzymes.
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