ArticleBritish journal of pharmacology2012
Effects of atorvastatin metabolites on induction of drug-metabolizing enzymes and membrane transporters through human pregnane X receptor.
Article in British journal of pharmacology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 54 citations in OpenAlex.
- The effect of atorvastatin treatment on serum oxysterol concentrations and cytochrome P450 3A4 activity.British journal of clinical pharmacology · 2015Trial
- Reengineering statin therapy to protect skeletal muscle: nanocarrier strategies for mitigating mitochondrial dysfunction and myotoxicity.Inflammation and regeneration · 2026Review
- Personalized statin therapy: Targeting metabolic processes to modulate the therapeutic and adverse effects of statins.Heliyon · 2025Review
- How Uremic Toxins Alter Atorvastatin Disposition: Molecular Mechanisms of Inhibition of the Enzyme CYP3A4.Balkan medical journal · 2025Article
- Potential Pharmacokinetic Interactions of Common Cardiovascular Drugs and Selected European and Latin American Herbal Medicines: A Scoping Review.Plants (Basel, Switzerland) · 2023Article
- Effect of polymorphisms in drug metabolism and transportation on plasma concentration of atorvastatin and its metabolites in patients with chronic kidney disease.Frontiers in pharmacology · 2023Article
- PXR activation impairs hepatic glucose metabolism partlyActa pharmaceutica Sinica. B · 2022Article
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- Pregnane X Receptor and the Gut-Liver Axis: A Recent Update.Drug metabolism and disposition: the biological fate of chemicals · 2022Review
- Effect of Statin Therapy on the Plasma Concentrations of Retinol, Alpha-Tocopherol and Coenzyme Q10 in Children with Familial Hypercholesterolemia.Cardiovascular drugs and therapy · 2022Article
- Regulation of PXR Function by Coactivator and Corepressor Proteins: Ligand Binding Is Just the Beginning.Cells · 2021Review
- Dexamethasone enhances the efficacy of atorvastatin in inhibiting excessively inflammation-induced abnormal angiogenesis by regulating macrophages.Journal of neuroinflammation · 2021Article
- Quantification of CYP3A and Drug Transporters Activity in Healthy Young, Healthy Elderly and Chronic Kidney Disease Elderly Patients by a Microdose Cocktail Approach.Frontiers in pharmacology · 2021Article
- The potential of Atorvastatin for chronic lung diseases therapy.Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society · 2020Review
- Impact of Plasma Exposure of Statins and Their Metabolites With Major Adverse Cardiovascular Events in Chinese Patients With Coronary Artery Disease.Frontiers in pharmacology · 2020Article
- Natural substance rutin versus standard drug atorvastatin in a treatment of metabolic syndrome-like condition.Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society · 2019Article
- Carboxymefloquine, the major metabolite of the antimalarial drug mefloquine, induces drug-metabolizing enzyme and transporter expression by activation of pregnane X receptor.Antimicrobial agents and chemotherapy · 2015Article
- Statins Increase Plasminogen Activator Inhibitor Type 1 Gene Transcription through a Pregnane X Receptor Regulated Element.PloS one · 2015Article
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Corrections and comments
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Authors and funding
7 authors at 5 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
background and purposeAtorvastatin metabolites differ in their potential for drug interaction because of differential inhibition of drug-metabolizing enzymes and transporters. We here investigate whether they exert differential effects on the induction of these genes via activation of pregnane X receptor (PXR) and constitutive androstane receptor (CAR). EXPERIMENTAL APPROACH: Ligand binding to PXR or CAR was analysed by mammalian two-hybrid assembly and promoter/reporter gene assays. Additionally, surface plasmon resonance was used to analyse ligand binding to CAR. Primary human hepatocytes were treated with atorvastatin metabolites, and mRNA and protein expression of PXR-regulated genes was measured. Two-hybrid co-activator interaction and co-repressor release assays were utilized to elucidate the molecular mechanism of PXR activation. KEY
resultsAll atorvastatin metabolites induced the assembly of PXR and activated CYP3A4 promoter activity. Ligand binding to CAR could not be proven. In primary human hepatocytes, the para-hydroxy metabolite markedly reduced or abolished induction of cytochrome P450 and transporter genes. While significant differences in co-activator recruitment were not observed, para-hydroxy atorvastatin demonstrated only 50% release of co-repressors. CONCLUSIONS AND IMPLICATIONS: Atorvastatin metabolites are ligands of PXR but not of CAR. Atorvastatin metabolites demonstrate differential induction of PXR target genes, which results from impaired release of co-repressors. Consequently, the properties of drug metabolites have to be taken into account when analysing PXR-dependent induction of drug metabolism and transport. The drug interaction potential of the active metabolite, para-hydroxy atorvastatin, might be lower than that of the parent compound.
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