Plasma levels and myocardial content of verapamil, norverapamil and two N-dealkyl-metabolites in man

Padrini, Roberto; Barbieri, Enrico; Piovan, Donatella; Toffoli, M; Motta, Antonino; Trevi, G. P.; Ferrari, Mariano

doi:10.1007/bf00607910

Cited by 13 publications

(6 citation statements)

References 15 publications

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“…The recent studies of Padrini et al (1985) on verapamil concentration in plasma and myocardium in patients undergoing cardiac surgery shed further light on the 'hysteresis' effect. It was found that mean M : P ratios for verapamil were approximately 7: 1 (comparable to the results of Keefe & Kates 1982).…”

Section: Uptake Of Verapamilmentioning

confidence: 97%

Myocardial Uptake of Drugs and Clinical Effects

Horowitz

Powell

1986

Clinical Pharmacokinetics

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The process of uptake of cardioactive drugs into the myocardium is a major determinant of the efficacy and potential toxicity of such agents. Evaluation of responses to anti-arrhythmic and positive inotropic agents is best performed with reference to their concentration in the myocardium, and the potential toxicity of drugs such as tricyclic antidepressants and anthracycline antineoplastics is likely to be related to peak myocardial drug concentrations. Although it has been appreciated for many years that even during long term drug administration the myocardial drug content may not be readily predictable on the basis of estimation of plasma drug concentrations, methodology for direct assessment of myocardial drug content has remained limited. The results of in vitro experiments, utilising tissue culture preparations of myocardial cells or isolated atria, have shed some light on the role of local factors as determinants of myocardial drug uptake. For many agents, attainment of maximal cardiac drug content in vitro is a very slow process (taking up to 3 hours), although maximal inotropic and electrophysiological effects may occur more rapidly. The prolonged time course of drug washout from these preparations also reflects their extensive and slow intracellular accumulation. Mechanical activity of the myocardium appears to accelerate drug uptake, particularly for otherwise slowly equilibrating agents, but the major determinant of the extent of drug uptake into isolated myocardial preparations is lipophilicity, perhaps reflecting the passage of drugs through the sarcolemma. In intact animals, assessment of myocardial drug content after acute drug administration has been performed utilising serial myocardial biopsy or sacrifice of animals. Studies in open-chested dogs suggest that acute accumulation of agents may be most closely predicted from the second compartment of a 3-compartment pharmacokinetic model, and that there is a variable correlation between changes in plasma and myocardial drug concentrations. For example, bretylium concentrations within the myocardium continue to increase for up to 6 hours after drug administration. Factors which may influence drug uptake into the myocardium in intact animals include ischaemia, which usually results in a delay in both drug uptake and subsequent clearance. This change can also be inferred from the time course of onset of antiarrhythmic drug effects in some models of myocardial ischaemia. Anoxia may also inhibit myocardial drug uptake.(ABSTRACT TRUNCATED AT 400 WORDS)

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Section: Uptake Of Verapamilmentioning

confidence: 97%

Myocardial Uptake of Drugs and Clinical Effects

Horowitz

Powell

1986

Clinical Pharmacokinetics

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“…According to data published by Padrini et al the mean myocardial plasma concentration ratio for verapamil was 7.05 with high inter-individual variability (range: 1.8-17.8). The ratio averaged 11.5 for norverapamil (range: 1.9-28), 8.93 for N-dealkylverapamil (range: 2.03-14.6) and 11.3 for N-dealkylnorverapamil (range: 0.87-23.9) [113]. Also, the relationship between plasma perhexiline concentrations and its uptake into the myocardium was explored by Drury et al [114].…”

Section: Cardiac Pharmaceutical Agentsmentioning

confidence: 99%

Plasma vs heart tissue concentration in humans – literature data analysis of drugs distribution

Tylutki

Polak

2015

Biopharm & Drug Disp

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ABSTRACT:Little is known about the uptake of drugs into the human heart, although it is of great importance nowadays, when science desires to predict tissue level behavior rather than to measure it. Although the drug concentration in cardiac tissue seems a better predictor for physiological and electrophysiological changes than its level in plasma, knowledge of this value is very limited. Tissue to plasma partition coefficients (Kp) come to rescue since they characterize the distribution of a drug among tissues as being one of the input parameters in physiologically based pharmacokinetic (PBPK) models. The article reviews cardiac surgery and forensic medical studies to provide a reference for drug concentrations in human cardiac tissue. Firstly, the focus is on whether a drug penetrates into heart tissue at a therapeutic level; the provided values refer to antibiotics, antifungals and anticancer drugs. Drugs that directly affect cardiomyocyte electrophysiology are another group of interest. Measured levels of amiodarone, digoxin, perhexiline and verapamil in different sites in human cardiac tissue where the compounds might meet ion channels, gives an insight into how these more lipophilic drugs penetrate the heart. Much data are derived from postmortem studies and they provide insight to the cardiac distribution of more than 200 drugs. The analysis depicts potential problems in defining the active concentration location, what may indirectly suggest multiple mechanisms involved in the drug distribution within the heart.

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“…It was considered to be a coronary vasodilator therefore its use started as an antianginal agent in 1962 in Germany [144]. The therapeutic plasma concentration of free verapamil (not bound to proteins) in humans is between 20-800 nM [145], although the mean myocardial to plasma concentration ratio was approximately seven suggesting accumulation of the drug in the heart [146]. Indeed, verapamil can accumulate in canine myocardium in a chamber specific manner showing greater accumulation in the ventricles compared to the atria without having left versus right-sided specific distribution [147].…”

Section: Phenylalkylaminesmentioning

confidence: 99%

Class IV Antiarrhythmic Agents: New Compounds Using an Old Strategy

Szentandrássy

Nagy²,

Hegyi³

et al. 2014

CPD

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Cardiac arrhythmias are a major cause of morbidity and mortality in the industrialized world. Among their treatment regimens one can find the calcium channel antagonists (CCAs), the class IV agents. In the cardiovascular system Land T-type calcium channels are found on vascular smooth muscle cells and cardiac myocytes with well defined physiological roles. Inhibition of calcium channels by CCAs has widely been used in clinical practice for several decades. Cardiovascular disorders are one of the many fields of medicine in which CCAs are used for various reasons and conditions. The three main indications of them are hypertension, angina and various cardiac arrhythmias. The most important classes of CCAs are dihydropyridines, phenylalkylamines and benzothiazepines but some newer compounds do not fall into any of these major classes. Dihydropyridines are not used in the antiarrhythmic therapy but are good vasodilators and antianginal agents. In contrast, phenylalkylamines and benzothiazepines exert cardiac actions in vivo and therefore these are one choice of antiarrhythmic drugs. This review focuses on phenylalkylamines, benzothiazepines and on new drugs with potential antiarrhythmic action in the heart as well as the mechanisms how calcium channels antagonism can lead to an antiarrhythmic action.

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Plasma levels and myocardial content of verapamil, norverapamil and two N-dealkyl-metabolites in man

Cited by 13 publications

References 15 publications

Myocardial Uptake of Drugs and Clinical Effects

Myocardial Uptake of Drugs and Clinical Effects

Plasma vs heart tissue concentration in humans – literature data analysis of drugs distribution

Class IV Antiarrhythmic Agents: New Compounds Using an Old Strategy

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