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Cyp 3A4 AND statin

Takeshi Hirota, Ichiro Ieiri
INTRODUCTION: Lipid-lowering drugs, especially hydroxymethylglutaryl-CoA reductase inhibitors (statins), are widely used in the treatment and prevention of atherosclerotic diseases. The benefits of statins are well documented. However, myotoxic side effects, which can sometimes be severe, including myopathy or rhabdomyolysis, have been associated with the use of statins. In some cases, this toxicity is associated with pharmacokinetic alterations. Potent inhibitors of CYP 3A4 significantly increase plasma concentrations of the active forms of simvastatin, lovastatin and atorvastatin...
2015: Expert Opinion on Drug Metabolism & Toxicology
Nicolas De Schryver, Xavier Wittebole, Peter Van den Bergh, Vincent Haufroid, Eric Goffin, Philippe Hantson
Simvastatin is among the most commonly used prescription medications for cholesterol reduction and the most common statin-related adverse drug reaction is skeletal muscle toxicity. Multiple factors have been shown to influence simvastatin-induced myopathy. In addition to age, gender, ethnicity, genetic predisposition, and dose, drug-drug interactions play a major role. This is particularly true for drugs that are extensively metabolized by cytochrome P450 (CYP)3A4. We describe a particularly severe case of rhabdomyolysis after the introduction of ciprofloxacin, a weak CYP3A4 inhibitor, in a patient who previously tolerated the simvastatin-amlodipine combination...
2015: Case Reports in Nephrology
E Berta, M Harangi, N Zsíros, E V Nagy, G Paragh, M Bodor
Statins are effective treatment for the prevention of cardiovascular diseases and used extensively worldwide. However, adverse effects induced by statins are the major barrier of maximalizing cardiovascular risk reduction. Hypothyroidism and administration of drugs metabolized on the same cytochrome P450 (CYPP450) pathways where statin biotransformation occurs represent a significant risk factor for statin induced adverse effects including myopathy. Simvastatin, atorvastatin and lovastatin are metabolized by CYP3A4, fluvastatin by CYP2C9, while rosuvastatin by CYP2C9 and 2C19...
June 2014: Die Pharmazie
Kyle A Davis, Marta A Miyares
PURPOSE: The pharmacology, pharmacokinetics, and clinical efficacy and safety of lomitapide in the management of homozygous familial hypercholesterolemia (HoFH) are reviewed. SUMMARY: Lomitapide (Juxtapid, Aegerion Pharmaceuticals) is an oral microsomal triglyceride transfer protein (MTP) inhibitor indicated for the treatment of patients with HoFH, a rare form of hypercholesterolemia that can lead to premature atherosclerotic disease. In clinical trials, the use of lomitapide alone or in combination with other lipid-lowering modalities reduced plasma concentrations of low-density lipoprotein cholesterol (LDL-C) by a mean of more than 50%...
June 15, 2014: American Journal of Health-system Pharmacy: AJHP
Timo Siepmann, Denise Heinke, Jessica Kepplinger, Kristian Barlinn, Siegmund Gehrisch, Xina Grählert, Uta Schwanebeck, Heinz Reichmann, Volker Puetz, Ulf Bodechtel, Georg Gahn
AIMS: Variability in responsiveness to clopidogrel is a clinical problem in secondary prevention after cerebral ischaemia which has been suggested to be linked to competitive metabolization of clopidogrel and cytochrome P450 (CYP) 3A4-oxidated statins such as simvastatin. We assessed the hypothesis that simvastatin, in contrast to CYP 2C9-metabolized fluvastatin, reduces clopidogrel-mediated platelet inhibition. METHODS: We performed a randomized, double-blind, double-dummy, two period crossover study in 13 patients with cerebral ischaemia (8F, 5 M), aged 64...
November 2014: British Journal of Clinical Pharmacology
K P Kerr, K E Mate, P J Magin, J Marley, N P Stocks, P Disler, C D Pond
WHAT IS KNOWN AND OBJECTIVE: The elderly are at increased risk of adverse effects resulting from drug interactions due to decreased drug clearance and polypharmacy. This study examines the prevalence of the co-administration of clinically relevant cytochrome P450 (CYP) enzyme inhibitors with drugs that are substrates for these enzymes, in the community-dwelling elderly in Australia. METHODS: Participants aged 75 years or older (n = 1045) were recruited via their general practitioners at four Australian sites (Newcastle, Sydney, Melbourne and Adelaide)...
August 2014: Journal of Clinical Pharmacy and Therapeutics
Yi-Ting Zhou, Lu-Shan Yu, Su Zeng, Yu-Wen Huang, Hui-Min Xu, Quan Zhou
BACKGROUND: Coadministration of 1,4-dihydropyridine calcium channel blockers (DHP-CCBs) with statins (or 3-hydroxy-3-methylglutaryl-coenzyme A [HMG-CoA] reductase inhibitors) is common for patients with hypercholesterolemia and hypertension. To reduce the risk of myopathy, in 2011, the US Food and Drug Administration (FDA) Drug Safety Communication set a new dose limitation for simvastatin, for patients taking simvastatin concomitantly with amlodipine. However, there is no such dose limitation for atorvastatin for patients receiving amlodipine...
2014: Therapeutics and Clinical Risk Management
Jung-Won Suh, Myung-Jin Cha, Seung-Pyo Lee, In-Ho Chae, Jang-Ho Bae, Taek-Geun Kwon, Jang-Whan Bae, Myeong-Chan Cho, Seung-Woon Rha, Hyo-Soo Kim
AIM: To compare the responsiveness to clopidogrel in patients who were prescribed two different types of statins, atorvastatin vs. rosuvastatin, following percutaneous coronary intervention. METHODS: A total of 915 patients were randomized according to the antiplatelet therapy strategy in the CILON-T trial. In this subgroup analysis, we included patients who took atorvastatin(20 mg/day, n=295) or rosuvastatin(10 mg/day, n=261) during the entire study period and underwent measurement of the P2Y12 reaction unit(PRU) values at both discharge and six months...
2014: Journal of Atherosclerosis and Thrombosis
Natasa Stojaković, Rajko Igić
INTRODUCTION: Statins have similar side effects that do not always occur at the same rate among the various statins. We present a case of simvastatin-induced muscle toxicity that disappeared when pravastatin was substituted for the original drug. CASE OUTLINE: A 74-year-old male, a nonsmoker, complained of severe nocturnal leg cramps. The patient also complained that similar painful cramping occurred when he walked rapidly or jogged. Because some components of his lipid panel exceeded the'desirable' range, and as he had a history of myocardial infarction, his family physician prescribed simvastatin (40 mg/day)...
May 2013: Srpski Arhiv za Celokupno Lekarstvo
Etienne P A Neve, Per Artursson, Magnus Ingelman-Sundberg, Maria Karlgren
The absorption, distribution, metabolism, and excretion (ADME) of drugs in vivo are to a large extent dependent on different transport and metabolism routes. Elucidation of this complex transport-metabolism interplay is a major challenge in drug development and at present no in vitro models suitable for this purpose are at hand. The aim of this study was to develop flexible, well-controlled, easy-to-use, integrated cell models, where drug transport and drug metabolism processes could be studied simultaneously...
August 5, 2013: Molecular Pharmaceutics
Joseph W Polli, Elizabeth Hussey, Mark Bush, Grant Generaux, Glenn Smith, David Collins, Susan McMullen, Nancy Turner, Derek J Nunez
1. This work investigated the drug interaction potential of GSK1292263, a novel GPR119 agonist, with the HMG-coA reductase inhibitors simvastatin and rosuvastatin. 2. In vitro experiments assessed the inhibition of transporters and CYP enzymes by GSK1292263, and a clinical drug interaction study investigated the effect of GSK1292263 (300 mg BID) on the pharmacokinetic profile of simvastatin (40 mg single dose) and rosuvastatin (10 mg single dose). 3. In vitro, GSK1292263 demonstrated little/weak inhibition (IC50 values >30 μM) towards CYPs (CYP1A2, 2C9, 2C19, 2D6, 3A4), Pgp, OATP1B3, or OCT2...
June 2013: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Miroslav Dostalek, Wai-Johnn Sam, Komal R Paryani, Joyce S Macwan, Reginald Y Gohh, Fatemeh Akhlaghi
BACKGROUND AND OBJECTIVE: Patients with diabetes mellitus might be at a higher risk of HMG-CoA reductase inhibitor (statin)-induced myotoxicity, possibly because of reduced clearance of the statin lactone. The present study was designed to investigate the effect of diabetes on the biotransformation of atorvastatin acid, both in vivo in nondiabetic and diabetic renal transplant recipients, and in vitro in human liver samples from nondiabetic and diabetic donors. SUBJECTS AND METHODS: A total of 312 plasma concentrations of atorvastatin acid and atorvastatin lactone, from 20 nondiabetic and 32 diabetic renal transplant recipients, were included in the analysis...
September 1, 2012: Clinical Pharmacokinetics
Makula Chandra Sekhar, P Jaya Chandra Reddy
Dyslipidemia is common in patients with type 2 diabetes. Statins are used as the first choice in treatment of diabetic dyslipidemia. Atorvastatin represents a first-line treatment option, alongside other hydroxyl methylglutaryl coenzyme A reductase inhibitors. Repaglinide is a short-acting, oral, insulin secretagogue that is used in the treatment of type 2 diabetes mellitus. Both the category of drugs undergo extensive metabolism with cytochrome enzyme system. This may lead to drug-drug interaction problems with altered repaglinide activity which is cautious...
May 2012: Molecular and Cellular Biochemistry
A Marot, J Morelle, V A Chouinard, M Jadoul, M Lambert, N Demoulin
Myopathy, including rhabdomyolysis, is a well-known, albeit rare complication of statin therapy. Predisposing factors include comorbidities and the concomitant use of cytochrome P-450 (CYP) 3A4 inhibitors. We report a case of severe simvastatin-induced rhabdomyolysis triggered by the addition of amiodarone to previously well-tolerated chronic statin therapy. Physicians should be aware of the risk of this potentially severe drug interaction. The dose of simvastatin should be reduced (to 20 mg daily) when concomitant treatment with amiodarone is required, or preference should be given to pravastatin, rosuvastatin or fluvastatin, which are not metabolised by the CYP 3A4...
March 2011: Acta Clinica Belgica
Cm Sultanpur, S Satyanarayana, Ns Reddy, Ke Kumar, S Kumar
Diabetes mellitus is a condition of increased blood glucose level in the body. Antihyperlipidemic drugs like statins and fibrates are widely used for prophylactic treatment in dyslipideamia and atherosclerosis. Diabetic dislipidemia exists with increased triglycerides, low HDL and high LDL levels. Hence, with oral hypoglycemic drugs, the addition of a lipid-lowering drug is necessary for controlling dislipidemia. In such a situation, there may be chances of drug-drug interactions between antidiabetic and antihyperlipidemic drugs...
April 2010: Journal of Young Pharmacists: JYP
Yaron Finkelstein, Steven E Aks, Janine R Hutson, David N Juurlink, Patricia Nguyen, Gal Dubnov-Raz, Uri Pollak, Gideon Koren, Yedidia Bentur
INTRODUCTION: Colchicine is used mainly for the treatment and prevention of gout and for familial Mediterranean fever (FMF). It has a narrow therapeutic index, with no clear-cut distinction between nontoxic, toxic, and lethal doses, causing substantial confusion among clinicians. Although colchicine poisoning is sometimes intentional, unintentional toxicity is common and often associated with a poor outcome. METHODS: We performed a systematic review by searching OVID MEDLINE between 1966 and January 2010...
June 2010: Clinical Toxicology
Pertti J Neuvonen
HMG-CoA reductase inhibitors (statins) can cause skeletal muscle toxicity; the risk of toxicity is elevated by drug interactions and pharmacogenetic factors that increase the concentration of statins in the plasma. Statins are substrates for several membrane transporters that may mediate drug interactions. Inhibitors of the organic anion transporting polypeptide 1B1 can decrease the hepatic uptake of many statins, as well as the therapeutic index of these agents. Potent inhibitors of cytochrome P450 (CYP)3A4 can significantly increase the plasma concentrations of the active forms of simvastatin, lovastatin and atorvastatin...
March 2010: Current Opinion in Investigational Drugs
Ya-Ling Han, Zi-Long Zhang, Yi Li, Shou-Li Wang, Quan-Min Jing, Zu-Lu Wang, Dong-Mei Wang
OBJECTIVE: To evaluate the long-term therapeutic effects of atorvastatin via cytochrome P450 (CYP)3A4 pathway or a non-CYP 3A4 pathway statin, pravastatin, combined with clopidogrel for the patients undergoing coronary stenting. METHODS: Between February 2006 and March 2007, a total of 1275 patients undergoing successful coronary stenting were randomly assigned to receive atorvastatin 20 mg/d (n = 638) or pravastatin 20 mg/d (n = 637). All patients received standard clopidogrel therapy...
August 25, 2009: Zhonghua Yi Xue za Zhi [Chinese medical journal]
Akihiro Hisaka, Makiko Kusama, Yoshiyuki Ohno, Yuichi Sugiyama, Hiroshi Suzuki
BACKGROUND AND OBJECTIVE: Pharmacokinetic drug-drug interactions (DDIs) are one of the major causes of adverse events in pharmacotherapy, and systematic prediction of the clinical relevance of DDIs is an issue of significant clinical importance. In a previous study, total exposure changes of many substrate drugs of cytochrome P450 (CYP) 3A4 caused by coadministration of inhibitor drugs were successfully predicted by using in vivo information. In order to exploit these predictions in daily pharmacotherapy, the clinical significance of the pharmacokinetic changes needs to be carefully evaluated...
2009: Clinical Pharmacokinetics
Sotir Polena, Manish P Gupta, Hafiza Shaikh, Kathleen Zazzali, Neil Coplan, Jonas Gintautas, Subir Singh Labana, Daniel Soffer
Clopidogrel therapy is the standard for prevention of cardiovascular thrombotic events. Clopidogrel is converted to an active thiol by the cytochrome P450 CYP 3A4 and 2C19 enzymes. Recent studies suggest that statins metabolized by CYP3A4 attenuate the anti-aggregatory effect of clopidogrel. We evaluated the effect of CYP3A4-metabolized statins (atorvastatin, group 1) and partially-CYP3A4-metabolized statins (simvastatin, group 2) on platelet aggregation inhibition (PAI) when given concomitantly with clopidogrel as compared to patients who were statin naive (group 3)...
2008: Proceedings of the Western Pharmacology Society
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