The interaction of diltiazem with simvastatin

Mousa, Omaima; Brater, D. Craig; Sundblad, Kimberly J.; Hall, Stephen D.

doi:10.1067/mcp.2000.104609

Cited by 117 publications

(69 citation statements)

References 35 publications

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“…In our study, a comparison of clinical characteristics between ADR and non-ADR groups (Table 1) showed that these risk factors do not appear to confound the genetic influence of the NR1I3 rs2307424 polymorphism, because frequencies in the groups were similar. With exception of calcium channel blocker use, that was more frequent in non-ADR group than in ADR patients, however, these drugs are classical CYP3A4 and glycoprotein P inhibitors, and might increase risk of adverse drug reaction (28)(29)(30). To the best of our knowledge, only one previous study (31) investigated the association of PPARA rs1800206 polymorphism with the lipid-lowering efficacy of statins; they found no association between PPARA rs1800206 genotypes and lipid baseline levels or lipid-lowering response to fluvastatin.…”

Section: Discussionmentioning

confidence: 99%

Influence of PPARA, RXRA, NR1I2 and NR1I3 gene polymorphisms on the lipid-lowering efficacy and safety of statin therapy

Lima

Bruxel

Hutz

et al. 2013

Arq Bras Endocrinol Metab

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OBJECTIVE: The aim of the present study was investigate the association between six genetic variants in the nuclear receptor genes PPARA, RXRA, NR1I2 and NR1I3 and the lipid-lowering efficacy and safety of statin therapy. SUBJECTS AND METHODS: The study was carried out on 240 Brazilian hypercholesterolemic patients on simvastatin and atorvastatin therapy. The polymorphisms were analyzed by PCR-based methods. RESULTS: The NR1I3 rs2307424 genotype distribution was different between subjects with and without adverse drug reactions. Among subjects in the ADR group, no T/T homozygotes were observed for this polymorphism, while in the non-ADR group the frequency of this genotype was 19.4% (P = 0.007, after multiple testing corrections P = 0.042). CONCLUSION: The polymorphisms investigated in PPARA (rs1800206), RXRA (rs11381416), and NR1I2 (rs1523130) did not influence the lipid-lowering efficacy and safety of statin. Our results show the possible influence of NR1I3 genetic variant on the safety of statin.

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Section: Discussionmentioning

confidence: 99%

Influence of PPARA, RXRA, NR1I2 and NR1I3 gene polymorphisms on the lipid-lowering efficacy and safety of statin therapy

Lima

Bruxel

Hutz

et al. 2013

Arq Bras Endocrinol Metab

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“…[79][80][81][82][83] In 10 healthy volunteers, diltiazem increased the Cmax of simvastatin by 3.6-fold and simvastatin acid by 3.7-fold (P<0.05). 84 The AUC of simvastatin was increased by 5-fold (P<0.05) and the elimination t 1/2 by 2.3-fold (P<0.05). In a study of 10 healthy volunteers, diltiazem significantly (P<0.05) increased the AUC of lovastatin by 3.6-fold and Cmax from 6±2 to 26±9 ng/mL but did not change the elimination t 1/2 .…”

Section: Diltiazem and Verapamilmentioning

confidence: 98%

Recommendations for Management of Clinically Significant Drug-Drug Interactions With Statins and Select Agents Used in Patients With Cardiovascular Disease: A Scientific Statement From the American Heart Association

Wiggins¹,

Saseen²,

Page³

et al. 2016

Circulation

249

194

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A drug-drug interaction (DDI) is a pharmacokinetic or pharmacological influence of 1 medication on another that differs from the known or anticipated effects of each agent alone.1 A DDI may result in a change in either drug efficacy or drug toxicity for 1 or both of the interacting medications.2 Pharmacokinetic DDIs result in altered absorption, distribution, metabolism, or excretion of a medication. A pharmacodynamic DDI occurs when 1 medication modifies the pharmacological effect of another in an additive, a synergistic, or an antagonistic fashion.It is estimated that ≈2.8% of hospital admissions occur as a direct result of DDIs. 3 However, the actual incidence of hospitalization secondary to clinically significant DDIs is likely to be highly underestimated because medication-related issues are more commonly reported as adverse drug reactions. Complex underlying disease states also may make recognizing a DDI more challenging, further contributing to a lower reported incidence. The overall clinical impact of a DDI can range from mild to life-threatening. Therefore, not all DDIs require a modification in therapy. The variability in the clinical significance of a DDI depends on both medication-specific and patient-specific factors. Medication-specific factors include the individual pharmacokinetic characteristics of each medication implicated in the DDI (eg, binding affinity, half-life [t 1/2 ]), dose of the medications, serum concentrations, timing and sequence of administration, and duration of therapy. Patient-specific factors include age, sex, lifestyle, genetic polymorphisms causing differences in enzyme expression or activity, and disease impairment affecting drug metabolism (eg, hepatic or renal impairment, cardiac failure) or predisposition to differences in efficacy or safety (eg, statin intolerance in patients with a history of myopathy). Clinically significant DDIs are usually preventable. To optimize patient safety, healthcare providers must have an understanding of the mechanisms, magnitude, and potential consequences of any given DDI. Interpreting this information will assist clinicians in the safe prescribing of medications and permits careful consideration of the benefits and risks of concomitant medications.Statins reduce morbidity and mortality in patients with known atherosclerotic cardiovascular disease (ASCVD) and in many primary prevention patients.4-9 Current guidelines recommend high-intensity statin therapy in all patients with ASCVD age ≤75 years and moderate-to high-intensity statin therapy in patients with ASCVD and age >75 years, diabetes mellitus, and familial hypercholesterolemia and in primary prevention patients with 10-year ASCVD risk ≥7.5%.10 Given the important role of statins in patients with ASCVD and those at high ASCVD risk, combination therapy with statins and other cardiovascular medications is highly likely, and potentially significant DDIs must be considered in patients treated with statins.Another important aspect of prescribing medications in combination is evalu...

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“…Using the model, the authors extrapolated the anticipated drug interaction between CYP3A substrates and fluoxetine, clarithromycin, and N-desmethyldiltiazem and claimed good qualitative agreement with the observed clinical interactions. Predicted values were 1.4, 2.6, and 4.7, respectively, with clinically observed values being 1.26 (Greenblatt et al, 1992), 3.5 to 9.6 (Yeates et al, 1996;Gorski et al, 1998), and 4.8 (Mousa et al, 2000), respectively. The underprediction of the clarithromycin/midazolam interaction can probably be ascribed to the contribution of intestinal metabolism in limiting the bioavailability of midazolam.…”

Section: The Science Of Time-dependent Inhibition and Predicting Ddimentioning

confidence: 99%

The Conduct of in Vitro Studies to Address Time-Dependent Inhibition of Drug-Metabolizing Enzymes: A Perspective of the Pharmaceutical Research and Manufacturers of America

Grimm

Einolf²,

Hall³

et al. 2009

Drug Metabolism and Disposition

284

246

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ABSTRACT:Time-dependent inhibition (TDI) of cytochrome P450 (P450) enzymes caused by new molecular entities (NMEs) is of concern because such compounds can be responsible for clinically relevant drug-drug interactions (DDI). Although the biochemistry underlying mechanism-based inactivation (MBI) of P450 enzymes has been generally understood for several years, significant advances have been made only in the past few years regarding how in vitro time-dependent inhibition data can be used to understand and predict clinical DDI. In this article, a team of scientists from 16 pharmaceutical research organizations that are member companies of the Pharmaceutical Research and Manufacturers of America offer a discussion of the phenomenon of TDI with emphasis on the laboratory methods used in its measurement. Results of an anonymous survey regarding pharmaceutical industry practices and strategies around TDI are reported. Specific topics that still possess a high degree of uncertainty are raised, such as parameter estimates needed to make predictions of DDI magnitude from in vitro inactivation parameters. A description of follow-up mechanistic experiments that can be done to characterize TDI are described. A consensus recommendation regarding common practices to address TDI is included, the salient points of which include the use of a tiered approach wherein abbreviated assays are first used to determine whether NMEs demonstrate TDI or not, followed by more thorough inactivation studies for those that do to define the parameters needed for prediction of DDI.Pharmacokinetic drug-drug interactions (DDIs) can occur when one drug alters the metabolism of a coadministered drug. The outcome is an increase or decrease in the systemic clearance and/or bioavailability, and a corresponding change in the exposure to a coadministered drug. The clinical consequences of DDIs range from lack of therapeutic efficacy of a life saving drug to severe adverse drug reactions, including fatalities. Significant drug-drug interactions can lead to termination of development of otherwise promising new therapies, withdrawal of a drug from the market, or severe restrictions/limitations on its use (Wienkers and Heath, 2005). Because of the impact on patient health and safety, DDI was the subject of a position paper in 2003 by scientists from member companies of the Pharmaceutical Research and Manufacturers of America (PhRMA) that focused on Article, publication date, and citation information can be found at

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The interaction of diltiazem with simvastatin

Abstract: Diltiazem coadministration resulted in a significant interaction with simvastatin, probably by inhibiting CYP3A-mediated metabolism. Concomitant use of diltiazem or other potent inhibitors of CYP3A with simvastatin should be avoided, or close clinical monitoring should be used.

Cited by 117 publications

References 35 publications

Influence of PPARA, RXRA, NR1I2 and NR1I3 gene polymorphisms on the lipid-lowering efficacy and safety of statin therapy

Influence of PPARA, RXRA, NR1I2 and NR1I3 gene polymorphisms on the lipid-lowering efficacy and safety of statin therapy

Recommendations for Management of Clinically Significant Drug-Drug Interactions With Statins and Select Agents Used in Patients With Cardiovascular Disease: A Scientific Statement From the American Heart Association

The Conduct of in Vitro Studies to Address Time-Dependent Inhibition of Drug-Metabolizing Enzymes: A Perspective of the Pharmaceutical Research and Manufacturers of America

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