Variability in Cytochrome P450-Mediated Metabolism of Cardiovascular Drugs: Clinical Implications and Practical Attempts to Avoid Potential Problems

Molden, Espen

doi:10.1159/000076934

Cited by 7 publications

(4 citation statements)

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“…The enzyme is also the most promiscuous P450 and contributes to the metabolism of approximately 50% of all pharmaceuticals on the market [33], including cyclosporin, bromocriptine, macrolide antibiotics [69], and statins [70]. Additionally, CYP3A4 is also the primary enzyme involved in food-drug interactions [71].…”

Section: X-ray Crystallography Of Cytochromes P450mentioning

confidence: 99%

Structural Features of Cytochromes P450 and Ligands that Affect Drug Metabolism as Revealed by X-Ray Crystallography and NMR

Roberts

Halpert

2010

Future Med. Chem.

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SUMMARYCytochromes P450 (P450s) play a major role in the clearance of drugs, toxins, and environmental pollutants. Additionally, metabolism by P450s can result in toxic or carcinogenic products. The metabolism of pharmaceuticals by P450s is a major concern during the design of new drug candidates. Determining the interactions between P450s and compounds of very diverse structures is complicated by the variability in P450-ligand interactions. Understanding the protein structural elements and the chemical attributes of ligands that dictate their orientation in the P450 active site will aid in the development of effective and safe therapeutic agents. The goal of this review is to describe P450-ligand interactions from two perspectives. The first is the various structural elements that microsomal P450s have at their disposal to assume the different conformations observed in X-ray crystal structures. The second is P450-ligand dynamics analyzed by NMR relaxation studies.

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Section: X-ray Crystallography Of Cytochromes P450mentioning

confidence: 99%

Structural Features of Cytochromes P450 and Ligands that Affect Drug Metabolism as Revealed by X-Ray Crystallography and NMR

Roberts

Halpert

2010

Future Med. Chem.

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“…The statins have different drug-drug interaction potentials due to different pharmacokinetic properties. Simvastatin, lovastatin and atorvastatin are all metabolized by cytochrome P450 3A4 (CYP3A4), whereas pravastatin and fluvastatin mainly have other eliminating pathways [13]. Many agents are inhibitors or inducers of CYP3A4, and the general interaction potential of simvastatin, lovastatin and atorvastatin is therefore higher than for other statins [8,10].…”

Section: Introductionmentioning

confidence: 99%

Co‐medication of statins and CYP3A4 inhibitors before and after introduction of new reimbursement policy

Devold

Molden

Furu

2009

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • HMG‐CoA reductase inhibitors (statins) are frequently used drugs in the treatment of dyslipidaemia. • Co‐medication with interacting drugs increases the risk of statin‐induced muscular side‐effects. • Simvastatin exhibits particularly high interaction potential due to substantial metabolism via cytochrome P450 3A4 (CYP3A4). WHAT THIS STUDY ADDS • In June 2005, a new reimbursement policy was introduced by the Norwegian Medicines Agency stating that simvastatin should be prescribed as first‐line lipid‐lowering therapy. • Following introduction of the new policy, the number of patients co‐medicated with simvastatin and CYP3A4 inhibitors almost doubled. • A potential consequence is increased incidence of muscular side‐effects in the statin‐treated population. AIMS To assess the prevalence of co‐medication of statins and CYP3A4 inhibitors before and after introduction of a new Norwegian reimbursement policy, which states that all patients should be prescribed simvastatin as first‐line lipid‐lowering therapy. METHODS Data from patients receiving simvastatin, lovastatin, pravastatin, fluvastatin or atorvastatin in 2004 and 2006, including co‐medication of potent CYP3A4 inhibitors, were retrieved from the Norwegian Prescription Database covering the total population of Norway. Key measurements were prevalence of continuous statin use (two or more prescriptions on one statin) and proportions of different statin types among all patients and those co‐medicated with CYP3A4 inhibitors. RESULTS In 2004, 5.9% (n= 272 342) of the Norwegian population received two or more prescriptions on one statin compared with 7.0% (n= 324 267) in 2006. The relative number of simvastatin users increased from 39.7% (n= 112 122) in 2004 to 63.1% (n= 226 672) in 2006. A parallel increase was observed within the subpopulation co‐medicated with statins and CYP3A4 inhibitors, i.e. from 42.9% (n= 7706) in 2004 to 63.6% (n= 13 367) in 2006. For all other statins the number of overall users decreased to a similar extent to those co‐medicated with CYP3A4 inhibitors. CONCLUSIONS In both 2004 and 2006, the choice of statin type did not depend on whether the patient used a CYP3A4 inhibitor or not. Considering the pronounced interaction potential of simvastatin with CYP3A4 inhibitors, a negative influence of the new policy on overall statin safety seems likely.

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“…[20][21][22][23][24][25][26] However, additional interacting drugs (e.g., diltiazem or cyclosporine) were involved in most of these cases. Despite the fact that atorvastatin may display less pharmacokinetic sensitivity to CYP3A4 inhibition than does simvastatin and lovastatin, 27 two cases of rhabdomyolysis have been reported after clarithromycin was added to atorvastatin treatment. 28,29 Other interacting drugs were also associated with these events.…”

Section: Discussionmentioning

confidence: 99%

Simvastatin‐Associated Rhabdomyolysis After Coadministration of Macrolide Antibiotics in Two Patients

Molden¹,

Andersson²

2007

Pharmacotherapy

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Two men, aged 83 and 78 years, who received stable therapy with simvastatin 80 mg/day were hospitalized 1-2 weeks after completion of short-term treatment with erythromycin and clarithromycin, respectively. Both patients were admitted with myalgia, muscle weakness, functional disability (inability to raise arms and legs), and serum creatine kinase levels more than 60 times the upper limit of normal (ULN). Substantial elevations in aspartate aminotransferase (> 30 times the ULN) and alanine aminotransferase (> 7 times the ULN) levels were also observed. Rhabdomyolysis was diagnosed in both patients. Both recovered, but the combined events resulted in almost 40 days of hospitalization, the cost of which is considerable. According to the Naranjo adverse drug reaction probability scale, the likelihood that the rhabdomyolysis was secondary to a simvastatin-macrolide interaction was probable. Four cases of rhabdomyolysis after therapy with combined simvastatin and clarithromycin have been reported previously, but this is apparently the first report of rhabdomyolysis after coadministration of erythromycin. The interacting mechanism likely was inhibited cytochrome P450 (CYP) 3A4 metabolism and possibly P-glycoprotein transport of simvastatin as well. Previous reports of simvastatin-clarithromycin-related events involved additional drugs that inhibited CYP3A4 and P-glycoprotein. However, this was not the situation with our two patients. To prevent future events, it is crucial that clinicians recognize the interaction risk associated with concurrent use of simvastatin and clarithromycin or erythromycin. The risk could be managed by temporary interruption of simvastatin treatment or administration of a noninteracting antimicrobial agent.

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Variability in Cytochrome P450-Mediated Metabolism of Cardiovascular Drugs: Clinical Implications and Practical Attempts to Avoid Potential Problems

Cited by 7 publications

References 162 publications

Structural Features of Cytochromes P450 and Ligands that Affect Drug Metabolism as Revealed by X-Ray Crystallography and NMR

Structural Features of Cytochromes P450 and Ligands that Affect Drug Metabolism as Revealed by X-Ray Crystallography and NMR

Co‐medication of statins and CYP3A4 inhibitors before and after introduction of new reimbursement policy

Simvastatin‐Associated Rhabdomyolysis After Coadministration of Macrolide Antibiotics in Two Patients

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