ArticlePharmaceutical research2006
Effects of acid and lactone forms of eight HMG-CoA reductase inhibitors on CYP-mediated metabolism and MDR1-mediated transport.
Article in Pharmaceutical research, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 92 citations in OpenAlex.
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- Pharmacological strategies to enhance the response of hepatoblastoma to chemotherapy through MDR1 inhibition.Acta pharmacologica Sinica · 2026Article
- Determination of the latent geometry of atorvastatin pharmacokinetics by transfer entropy to identify bottlenecks.BMC pharmacology & toxicology · 2025Article
- Personalized statin therapy: Targeting metabolic processes to modulate the therapeutic and adverse effects of statins.Heliyon · 2025Review
- Predicting disruptions to drug pharmacokinetics and the risk of adverse drug reactions in non-alcoholic steatohepatitis patients.Acta pharmaceutica Sinica. B · 2023Review
- SLCO1B1 Phenotype and CYP3A5 Polymorphism Significantly Affect Atorvastatin Bioavailability.Journal of personalized medicine · 2021Article
- P-Glycoprotein Inhibition Exacerbates Paclitaxel Neurotoxicity in Neurons and Patients With Cancer.Clinical pharmacology and therapeutics · 2020Article
- Review
- Association between statin use and ischemic stroke or major hemorrhage in patients taking dabigatran for atrial fibrillation.CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne · 2017Article
- Effects of silymarin on the pharmacokinetics of atorvastatin in diabetic rats.European journal of drug metabolism and pharmacokinetics · 2014Article
- Pharmacoepidemiologic and in vitro evaluation of potential drug-drug interactions of sulfonylureas with fibrates and statins.British journal of clinical pharmacology · 2014Article
- Effect of pitavastatin on vascular reactivity in hypercholesterolemic rabbits.Arquivos brasileiros de cardiologia · 2014Article
- Potential statin-drug interactions: prevalence and clinical significance.SpringerPlus · 2014Article
- The administration of pitavastatin augments creatinine clearance associated with reduction in oxidative stress parameters: acute and early effects.Clinical and experimental nephrology · 2013Article
- Concomitant administration of simvastatin with ivabradine in contrast to metoprolol intensifies slowing of heart rate in normo- and hypercholesterolemic rats.Archives of medical science : AMS · 2012Article
- Pleiotropic effects of pitavastatin.British journal of clinical pharmacology · 2012Review
- Effects of atorvastatin metabolites on induction of drug-metabolizing enzymes and membrane transporters through human pregnane X receptor.British journal of pharmacology · 2012Article
- Does rosuvastatin increase serum levels of 25-hydroxy-vitamin D?Dermato-endocrinology · 2012Article
- A systems biology approach to dynamic modeling and inter-subject variability of statin pharmacokinetics in human hepatocytes.BMC systems biology · 2011Article
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
purposeWith the growing clinical usage of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), the number of reports concerning serious drug-drug interaction has been increasing. Because recent studies have shown that conversion between acid and lactone forms occurs in the body, drug-drug interaction should be considered on both acid and lactone forms. Thus, we investigated the inhibitory effects of acid and lactone forms of eight statins, including one recently withdrawn, cerivastatin, and two recently developed, pitavastatin and rosuvastatin, on cytochrome P450 (CYP) 2C8, CYP2C9, and CYP3A4/5 metabolic activities and multidrug resistance protein 1 (MDR1) transporting activity.
methodsThe inhibitory effects of statins on CYP metabolic activities and MDR1 transporting activity were investigated using human liver microsomes and MDR1-overexpressing LLC-GA5-COL150 cells, respectively.
resultsThe acid forms had minimal inhibitory effects on all CYP activities tested, except for fluvastatin on CYP2C9-mediated tolbutamide 4-hydroxylation (IC50 = 1.7 microM) and simvastatin on CYP3A4/5-mediated paclitaxel 3-hydroxylation (12.0 microM). Lactone forms showed no or minimal inhibitory effects on CYP2C8, CYP2C9, and CYP2C19 activities, except for rosuvastatin on the CYP2C9 activity (20.5 microM), whereas they showed stronger inhibitory effects on the CYP3A4/5 activity with the rank order of atorvastatin (5.6 microM), cerivastatin (8.1 microM), fluvastatin (14.9 microM), simvastatin (15.2 microM), rosuvastatin (20.7 microM), and lovastatin (24.1 microM). Pitavastatin and pravastatin had little inhibitory effect, and a similar order was found also for testosterone 6beta-hydroxylation. MDR1-mediated transport of [3H]digoxin was inhibited only by lactone forms, and the rank order correlated with that of inhibitory effects on both CYP3A4/5 activities. Inhibitory effects on MDR1 activity, and on both CYP3A4/5 activities, could be explained by the lipophilicity; however, a significant correlation was found between the lipophilicity and inhibitory effects on CYP2C8-mediated paclitaxel 6alpha-hydroxylation.
conclusionsWe showed the difference between the acid and lactone forms in terms of drug interaction. The lipophilicity could be one of the important factors for inhibitory effects. In the case of statins, it is important to examine the effects of both forms to understand the events found in clinical settings, including the pleiotropic effects.
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