ArticleDrug metabolism and disposition: the biological fate of chemicals2013
Effect of CYP3A5 expression on the inhibition of CYP3A-catalyzed drug metabolism: impact on modeling CYP3A-mediated drug-drug interactions.
Article in Drug metabolism and disposition: the biological fate of chemicals, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 36 citations in OpenAlex.
- Assessment of the Intestinal CYP3A Contribution to Drug Interactions with Extended-Release Tacrolimus (LCPT) Using Grapefruit Juice.Clinical pharmacology in drug development · 2026Trial
- Quantitative Prediction of CYP3A4- and CYP3A5-Mediated Drug Interactions.Clinical pharmacology and therapeutics · 2020Trial
- A randomised study of the effect of danoprevir/ritonavir or ritonavir on substrates of cytochrome P450 (CYP) 3A and 2C9 in chronic hepatitis C patients using a drug cocktail.European journal of clinical pharmacology · 2013Trial
- Deconvoluting Gut Versus Liver Cytochrome P450 3A4 Function: Drug Probes, Biomarkers, and Tissue Biopsy.Journal of clinical pharmacology · 2026Review
- Inhibition of Tacrolimus Metabolism by Cannabidiol and Its Metabolites In Vitro.Clinical and translational science · 2025Article
- Guidance on Selecting Optimal Steady-State Tacrolimus Concentrations for Continuous IV Perfusion: Insights from Physiologically Based Pharmacokinetic Modeling.Pharmaceuticals (Basel, Switzerland) · 2024Article
- A Review of CYP-Mediated Drug Interactions: Mechanisms and In Vitro Drug-Drug Interaction Assessment.Biomolecules · 2024Review
- Arsenic: A Perspective on Its Effect on Pioglitazone Bioavailability.International journal of environmental research and public health · 2023Article
- Article
- The Segregated Intestinal Flow Model (SFM) for Drug Absorption and Drug Metabolism: Implications on Intestinal and Liver Metabolism and Drug-Drug Interactions.Pharmaceutics · 2020Review
- Drug interactions between tacrolimus and clotrimazole troche: a data mining approach followed by a pharmacokinetic study.European journal of clinical pharmacology · 2020Article
- Cytochrome P450 and flavin-containing monooxygenase families: age-dependent differences in expression and functional activity.Pediatric research · 2018Article
- Effects of CYP3A5 genetic polymorphism and smoking on the prognosis of non-small-cell lung cancer.OncoTargets and therapy · 2016Article
- Effect of CYP3A5 and ABCB1 polymorphisms on the interaction between tacrolimus and itraconazole in patients with connective tissue disease.European journal of clinical pharmacology · 2015Article
- Nuclear Receptors in Drug Metabolism, Drug Response and Drug Interactions.Nuclear receptor researchArticle
Corrections and comments
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Authors and funding
7 authors at 4 institutions in 2 countries.
Funding
Abstract
The purpose of this study was to determine the impact of CYP3A5 expression on inhibitory potency (Ki or IC50 values) of CYP3A inhibitors, using recombinant CYP3A4 and CYP3A5 (rCYP3A4 and rCYP3A5) and CYP3A5 genotyped human liver microsomes (HLMs). IC50 ratios between rCYP3A4 and rCYP3A5 (rCYP3A5/rCYP3A4) of ketoconazole (KTZ) and itraconazole (ITZ) were 8.5 and 8.8 for midazolam (MDZ), 4.7 and 9.1 for testosterone (TST), 1.3 and 2.8 for terfenadine, and 0.6 and 1.7 for vincristine, respectively, suggesting substrate- and inhibitor-dependent selectivity of the two azoles. Due to the difference in the IC50 values for CYP3A4 and CYP3A5, nonconcordant expression of CYP3A4 and CYP3A5 protein can significantly affect the observed magnitude of CYP3A-mediated drug-drug interactions in humans. Indeed, the IC50 values of KTZ and ITZ for CYP3A-catalyzed MDZ and TST metabolism were significantly higher in HLMs with CYP3A5*1/*1 and CYP3A5*1/*3 genotypes than in HLMs with the CYP3A5*3/*3 genotype, showing CYP3A5 expression-dependent IC50 values. Moreover, when IC50 values of KTZ and ITZ for different HLMs were kinetically simulated based on CYP3A5 expression level and enzyme-specific IC50 values, a good correlation between the simulated and the experimentally measured IC50 values was observed. Further simulation analysis revealed that both the Ki ratio (for inhibitors) and Vmax/Km ratio (for substrates) between CYP3A4 and CYP3A5 were major factors for CYP3A5 expression-dependent IC50 values. In conclusion, the present study demonstrates that CYP3A5 genotype and expression level have a significant impact on inhibitory potency for CYP3A-catalyzed drug metabolism, but that the magnitude of its effect is inhibitor-substrate pair specific.
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