Metabolic syndrome potentiates the cardiac action potential-prolonging action of drugs: A possible ‘anti-proarrhythmic’ role for amlodipine

Caillier, Bertrand; Pilote, Sylvie; Patoine, Dany; Levac, Xavier; Couture, Christian; Daleau, Pascal; Simard, Chantale; Drolet, Benoît

doi:10.1016/j.phrs.2011.11.015

Cited by 15 publications

(14 citation statements)

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“…Guinea pig models of diet-induced metabolic syndrome were developed in our laboratory as described previously (Caillier et al, 2012) (Charles River Laboratories, Montréal, QC, Canada). These experiments were carried out in accordance with the Declaration of Helsinki and with the Guide to the Care and Use of Experimental Animals of the Canadian Council on Animal Care.…”

Section: Downloaded Frommentioning

confidence: 99%

Decreased CYP3A Expression and Activity in Guinea Pig Models of Diet-Induced Metabolic Syndrome: Is Fatty Liver Infiltration Involved?

et al. 2013

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Background: In humans, CYP3A drug-metabolizing enzyme subfamily is the most important. Numerous pathophysiological factors, such as diabetes and obesity, were shown to affect CYP3A activity. Often considered a precursor state for type II diabetes, metabolic syndrome exerts a modulating role on CYP3A, in our hypothesis. Objective: To evaluate the effect of metabolic syndrome on CYP3A drug-metabolizing activity/expression in guinea pigs. Methods: Hepatic microsomes were prepared from male Hartley guinea pigs fed with a control, a high-fat high sucrose (HFHS) or a high-fat high fructose diet (HFHF). Domperidone was selected as a probe substrate of CYP3A and formation of four of its metabolites was evaluated using high-performance liquid chromatography. CYP3A protein and mRNA expression were assessed by Western blot and reverse-transcription quantitative polymerase chain reaction, respectively. Hepatic fatty infiltration was evaluated using standard Oil Red O staining. Triglyceride and free fatty acid liver content were also quantified. Results: Microsomal CYP3A activity was significantly decreased in both HFHS and HFHF diet groups versus the control diet group. Significant decreases of CYP3A mRNA and protein expression were observed in both HFHS and HFHF diet groups. Oil Red O staining showed a massive liver fatty infiltration in the HFHS and HFHF diet groups, which was not observed in the control diet group. Both triglyceride and free fatty acid liver content were significantly increased in the HFHS and HFHF diet groups. Conclusion: Diet-induced metabolic syndrome decreases CYP3A expression/activity in guinea pigs. This may ultimately lead to variability in drug response, ranging from lack of effect to life-threatening toxicity.Introduction CYP3A4, the most abundant cytochrome P450 enzyme in the human liver and small intestine, is responsible for the metabolism of about 50% of all marketed drugs (Danielson, 2002). There is a considerable variability in the expression and activity of CYP3A4 among the general population (10-to 100-fold), which cannot be solely explained by genetic factors (Elens et al., 2011). There is evidence that diseases or pathologic states may modulate human and animal CYP3A (Yoshinari et al., 2006;Dostalek et al., 2011). The variability in CYP3A4-associated drug metabolism is known as a major determinant of drug response and/or toxicity (Lamba et al., 2002). Currently, more than 30% of the United States population has a body mass index . 30 kg/m 2 , which puts those people in the obese category (Ogden et al., 2006). Ninety percent of obese patients present histologically proven fatty liver infiltration-related abnormalities (Moretto et al., 2003). Some pharmacokinetic studies performed in obese populations reported a significant decrease in the clearance of drugs, particularly when it is CYP3A-mediated (Abernethy et al., 1984;Caraco et al., 1995). Diabetes is a widespread chronic disease, which was affecting over 350 million people worldwide in 2011 (Whiting et al., 2011). Common como...

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confidence: 99%

Decreased CYP3A Expression and Activity in Guinea Pig Models of Diet-Induced Metabolic Syndrome: Is Fatty Liver Infiltration Involved?

et al. 2013

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“…As previously mentioned, our laboratory showed that amlodipine, a calcium channel blocker, reduces the cardiac action potentialprolonging effect of dofetilide [14], suggesting a potential reduction of its proarrhythmic properties, thus suggesting a rationale for using these two drugs simultaneously. This HPLC method was therefore developed in order to further study ex vivo and in vivo drug-drug interaction between dofetilide and amlodipine in guinea pigs.…”

Section: Recovery (%) For Dofetilide At Three Concentrations (N=3)mentioning

confidence: 56%

“…As we demonstrated ex vivo in guinea pig hearts, the coadministration of both drugs could be beneficial in reducing the cardiac proarrhythmic potential of dofetilide [14]. Therefore, it could be very interesting to conduct a study in humans to confirm these exciting results.…”

Section: Recovery (%) For Dofetilide At Three Concentrations (N=3)mentioning

confidence: 72%

“…All these agents cause a lower incidence of TDP and are more potent at suppressing ventricular arrhythmias. Along those lines, our laboratory has recently shown that amlodipine, a calcium channel blocker, reduces the monophasic APD-prolonging effect of dofetilide [14], suggesting a potential reduction of its proarrhythmic properties and the possible rationale for using both drugs simultaneously.…”

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Simultaneous Determination of Dofetilide and Amlodipine in Plasma by HPLC

Kaddar¹,

Pilote²,

Wong³

et al. 2013

J Chromat Separation Techniq

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Dofetilide is a Class III antiarrhythmic drug useful in the management of atrial fibrillation but also known to prolong the QT interval on the ECG and to induce malignant ventricular tachyarrhythmias such as torsades de pointes (TDP). Drugs with calcium channel-blocking properties contribute to decrease the incidence of TDP. Amlodipine is a dihydropyridine calcium channel antagonist. Considering the potentially safe and useful combined use of dofetilide and amlodipine, we undertook drug biotransformation studies. To perform studies aiming to evaluate the possible pharmacokinetic interaction between these drugs, a unique sensitive HPLC assay able to quantify both drugs simultaneously was required. A sensitive and specific HPLC method using a tandem of UV/fluorescence detection was described for the analysis of amlodipine and dofetilide in plasma. The within-day and between-day precision studies showed good reproducibility with coefficients of variation less than 10% for all the analytes. The limits of detection were 0.5 ng/mL and 0.25 ng/mL and the limit of quantification were 1.7 ng/mL and 0.8 ng/mL for dofetilide and amlodipine respectively. This new method could be of great value in many applications such as in vitro and in vivo pharmacokinetic and drug-drug interactions studies, as well as therapeutic drug monitoring.

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“…More studies are requested to explore lipid-lipoprotein profiles of guinea pigs that received a maternal HFD. Caillier and colleagues [106] currently generated a guinea pig model of MetS by 150-day exposure to diabetogenic high fat high sucrose or the high fat high fructose diets. To my knowledge, it would be early to consider guinea pig as an animal model of MetS since the literatures are scarce.…”

Section: The Guinea Pig Modelsmentioning

confidence: 99%

Animal Models as Tools for Translational Research: Focus on Atherosclerosis, Metabolic Syndrome and Type-II Diabetes Mellitus

Karimi¹

2012

Lipoproteins - Role in Health and Diseases

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Metabolic syndrome potentiates the cardiac action potential-prolonging action of drugs: A possible ‘anti-proarrhythmic’ role for amlodipine

Cited by 15 publications

References 40 publications

Decreased CYP3A Expression and Activity in Guinea Pig Models of Diet-Induced Metabolic Syndrome: Is Fatty Liver Infiltration Involved?

Decreased CYP3A Expression and Activity in Guinea Pig Models of Diet-Induced Metabolic Syndrome: Is Fatty Liver Infiltration Involved?

Simultaneous Determination of Dofetilide and Amlodipine in Plasma by HPLC

Animal Models as Tools for Translational Research: Focus on Atherosclerosis, Metabolic Syndrome and Type-II Diabetes Mellitus

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