Cited by 796Lipoproteins and Cardiovascular HealthCholesterol and Lipid MetabolismCancer, Lipids, and Metabolism

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New insights into the pharmacodynamic and pharmacokinetic properties of statins

Corsini, Alberto, Bellosta, Stefano, Baetta, Roberta, Fumagalli, Remo, Paoletti, Rodolfo, Bernini, Franco·1999·Pharmacology & Therapeutics

DOI 10.1016/s0163-7258(99)00045-5

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Abstract

The beneficial effects of statins are assumed to result from their ability to reduce cholesterol biosynthesis. However, because mevalonic acid is the precursor not only of cholesterol, but also of many nonsteroidal isoprenoid compounds, inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase may result in pleiotropic effects. It has been shown that several statins decrease smooth muscle cell migration and proliferation and that sera from fluvastatin-treated patients interfere with its proliferation. Cholesterol accumulation in macrophages can be inhibited by different statins, while both fluvastatin and simvastatin inhibit secretion of metalloproteinases by human monocyte-derived macrophages. The antiatherosclerotic effects of statins may be achieved by modifying hypercholesterolemia and the arterial wall environment as well. Although statins rarely have severe adverse effects, interactions with other drugs deserve attention. Simvastatin, lovastatin, cerivastatin, and atorvastatin are biotransformed in the liver primarily by cytochrome P450-3A4, and are susceptible to drug interactions when co-administered with potential inhibitors of this enzyme. Indeed, pharmacokinetic interactions (e.g., increased bioavailability), myositis, and rhabdomyolysis have been reported following concurrent use of simvastatin or lovastatin and cyclosporine A, mibefradil, or nefazodone. In contrast, fluvastatin (mainly metabolized by cytochrome P450-2C9) and pravastatin (eliminated by other metabolic routes) are less subject to this interaction. Nevertheless, a 5- to 23-fold increase in pravastatin bioavailability has been reported in the presence of cyclosporine A. In summary, statins may have direct effects on the arterial wall, which may contribute to their antiatherosclerotic actions. Furthermore, some statins may have lower adverse drug interaction potential than others, which is an important determinant of safety during long-term therapy.

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Authors: Corsini, A., Bellosta, S., Baetta, R., Fumagalli, R., Paoletti, R., & Bernini, F.
Affiliations: University of Milan (IT)
University of Parma (IT)
Corresponding author: Corsini, Alberto
ORCID: Corsini, Alberto
Bellosta, Stefano
Baetta, Roberta
Venue: Pharmacology & Therapeutics
Publisher: Elsevier BV
Published: 1999-12
Volume: 84
Issue: 3
Pages: 413-428
ISSN: 0163-7258 (ISSN-L)
DOI: 10.1016/s0163-7258(99)00045-5
OpenAlex: W2045063002
Cited by: 796
References: 186
Citations by year: 2026: 5 · 2025: 6 · 2024: 27 · 2023: 19 · 2022: 17 · 2021: 25 · 2020: 17 · 2019: 14 · 2018: 21 · 2017: 30 · 2016: 30 · 2015: 27 · 2014: 35 · 2013: 31 · 2012: 38
FWCI: 5.97
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Pharmacology & Therapeutics (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
Keywords: statins, pharmacokinetics, pharmacodynamics, HMG-CoA reductase inhibition, mevalonate, pleiotropy, smooth muscle cell proliferation, macrophage cholesterol accumulation, atherosclerosis, drug interactions, CYP3A4, cyclosporine, rhabdomyolysis, myositis, pravastatin, fluvastatin, simvastatin, lovastatin, atorvastatin, cerivastatin
MeSH terms: Atorvastatin, Fluvastatin, Animals, Anticholesteremic Agents, Cell Division, Cytochrome P-450 Enzyme System, Drug Interactions, Fatty Acids, Monounsaturated, Heptanoic Acids, Humans, Indoles, Mevalonic Acid, Pyridines, Pyrroles, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Simvastatin

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New insights into the pharmacodynamic and pharmacokinetic properties of statins

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