Pharmacokinetics and metabolism of dofetilide in mouse, rat, dog and man

Smith, Dennis A.; Rasmussen, H. S.; Stopher, D. A.; Walker, Don K.

doi:10.3109/00498259209053133

Cited by 60 publications

(32 citation statements)

References 11 publications

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“…We recognize that these concentrations of dofetilide are greater than those typically measured in the plasma of adult patients taking dofetilide therapeutically. 39,40 In contrast to our expectations, prolongation of APD by dofetilide did not change the amplitude of calcium transients in either neonates or adults. In adult cells, dofetilide (0.1, 1, and 10 mM) increased APD, but despite the increase in APD, there is reportedly no change in calcium current.…”

Section: Effects Of Dofetilide On Ap and Calcium Transientscontrasting

confidence: 84%

Paradoxical Effect of Dofetilide on Action Potential Duration and Calcium Transient Amplitude in Newborn Rabbit Ventricular Myocytes

Srivastava

Collis

et al. 2005

Journal of Cardiovascular Pharmacology

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The Na+-Ca2+ exchanger (NCX) is up-regulated in the neonatal rabbit heart. Because the duration of membrane depolarization is an important determinant of calcium entry via NCX, pharmacological agents that lengthen the action potential (AP) may significantly increase the amount of activator calcium in newborns. We tested this potentially novel therapeutic strategy by using action potential voltage clamp steps or using dofetilide, a blocker of IKr, to prolong the action potential duration (APD). The effects of changing APD on calcium transients were determined in ventricular myocytes at different developmental stages: newborn (1-4 days), juvenile (9-10 days), and adult ventricular myocytes (35 degrees C; 1 Hz). Calcium transient amplitude in neonatal myocytes increased substantially with clamping with longer APs. In contrast, exposure to dofetilide (0.1, 1, and 10 microM) under current clamp conditions increased APD in a concentration-dependent manner but had no significant effect on calcium transient amplitude in either neonates or adults. When the AP was held constant under voltage clamp conditions, dofetilide decreased the calcium transient amplitude in neonates. This effect is likely related to inhibition of sodium-calcium exchanger and L-type Ca2+ currents (ICa), as observed in separate experiments. These results suggest that dofetilide has a paradoxical effect on APD and calcium transients in the newborn heart.

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Section: Effects Of Dofetilide On Ap and Calcium Transientscontrasting

confidence: 84%

Paradoxical Effect of Dofetilide on Action Potential Duration and Calcium Transient Amplitude in Newborn Rabbit Ventricular Myocytes

Srivastava

Collis

et al. 2005

Journal of Cardiovascular Pharmacology

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“…16,17 Pharmacokinetics Dofetilide is well absorbed after oral administration, with an absolute bioavailability of Ͼ90%. [41][42][43][44] Ingestion with food delays absorption but does not affect total bioavailability. Peak plasma concentrations are seen 2 to 3 hours after ingestion in fasted subjects.…”

Section: Effects Of Dofetilide On Arrhythmias In Animal Modelsmentioning

confidence: 99%

Dofetilide

2000

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Dofetilide is a new antiarrhythmic drug that recently was recommended for approval by an advisory committee to the Food and Drug Administration (FDA) for treatment of patients with persistent atrial fibrillation. Dofetilide is a specific blocker of the rapid component of the outward delayed rectifier potassium current I Kr and will represent the first drug with relatively pure class III antiarrhythmic properties to be widely released. Basic ElectrophysiologyCardiac depolarization results principally from the flow of inward Na ϩ and Ca 2ϩ ions as the rapid and slow inward currents. Repolarization results from a balance between inactivation of the slow inward current and activation of repolarizing predominantly K ϩ currents. Early repolarization results from a transient outward current, I TO , which is activated rapidly by membrane depolarization. Terminal repolarization is mediated by outward delayed rectifier K ϩ currents, I K , which are activated slowly (over a period of 200 to 300 ms) on membrane depolarization and turn off, or deactivate, relatively slowly on membrane repolarization.I K can be separated pharmacologically into 2 components: a rapidly activating component, I Kr , and a slower component, I Ks , each carried by a separate ion channel molecule. 1,2 HERG channels are responsible for I Kr , whereas I Ks flows through KvLQT1 channels. Specific blockers of I Kr are therefore classified as pure class III antiarrhythmic agents because they produce only prolongation of action potential duration (and hence of QT interval). These actions may result in arrhythmia termination or suppression but can also lead to excess QT prolongation and polymorphic ventricular tachycardia. Examples of specific I Kr blockers include the methanesulfonanilide agents dofetilide, E4031, almokalant, and D-sotalol. Effects of Dofetilide on I krDofetilide blocks I Kr in all myocardial tissues with high potency (50% effective concentration [EC 50 ] in the nanomolar range). Block is voltage dependent and most prominent at depolarized potentials. 1,3,4 It does not occur in resting muscle but rather develops on depolarization. 1,5 Recovery from block is also potential dependent and is very slow at hyperpolarized potentials close to the resting potential. 1 Steady-state block at any dose is constant and does not change with increasing heart rate 1,3 because the recovery time is much greater than the diastolic interval. 1 Dofetilide block of I Kr increases as extracellular potassium concentration ([K]o) is reduced. 6 This sensitivity of dofetilide block to [K]o is of obvious clinical importance. Even moderate hypokalemia would be expected to disproportionately increase action potential prolongation induced by dofetilide, and correction of hypokalemia is of crucial importance in treating QT prolongation and torsade de pointes caused by I Kr blockade. Conversely, hyperkalemia blunts the effect of dofetilide, 7 suggesting the possibility of reduced efficacy after acute coronary occlusion or during rapid heart rates, when local cardiac tis...

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“…To assess the overall performance of the model in terms of successfully predicting in vivo plasma levels, the plasma concentration wMLFE was determined for both the training and test sets; this (Ryrfeldt et al, 1982;Grimaldi et al, 1986;Coyle et al, 1991;Smith et al, 1992). The simulated data are the median values (solid line) of a population of predicted profiles generated from 100 stochastic simulations; also indicated are the 10th (dashed line) and 90th (dotted line) percentiles of the population.…”

Section: Resultsmentioning

confidence: 99%

Application of a Generic Physiologically Based Pharmacokinetic Model to the Estimation of Xenobiotic Levels in Human Plasma

Brightman¹,

Leahy²,

Searle³

et al. 2005

Drug Metab Dispos

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ABSTRACT:Estimation of xenobiotic kinetics in humans frequently relies upon extrapolation from experimental data generated in animals. In an accompanying paper, we have presented a unique, generic, physiologically based pharmacokinetic model and described its application to the prediction of rat plasma pharmacokinetics from in vitro data alone. Here we demonstrate the application of the same model, parameterized for human physiology, to the estimation of plasma pharmacokinetics in humans and report a comparative evaluation against some recently published predictive methods that involve scaling from in vivo animal data. The model was parameterized through an optimization process, using a training set of in vivo data taken from the literature, and validated using a separate test set of published in vivo data. On average, the vertical divergence of the predicted plasma concentrations from the observed data, on a semilog concentration-time plot, was 0.47 log unit. For the training set, more than 80% of the predicted values of a standardized measure of the area under the concentration-time curve were within 3-fold of the observed values; over 70% of the test set predictions were within the same margin. Furthermore, in terms of predicting human clearance for the test set, the model was found to match or exceed the performance of three published interspecies scaling methods, all of which showed a distinct bias toward overprediction. We conclude that the generic physiologically based pharmacokinetic model, as a means of integrating readily determined in vitro and/or in silico data, is potentially a powerful, cost-effective tool for predicting human xenobiotic kinetics in drug discovery and risk assessment.Physiologically based pharmacokinetic (PBPK) models are mathematical descriptions of the flow of blood throughout the body, developed for the simulation of xenobiotic absorption, distribution, and elimination. Such models have been used by scientists from a number of different disciplines who are interested in the simulation and prediction of exposure (Grass and Sinko, 2002;Leahy, 2003).The application of a generic form of a PBPK model to the prediction of xenobiotic plasma levels in rat following an intravenous dose has been reported in an accompanying publication (Brightman et al., 2006). Here we describe the work that we have done to parameterize the same PBPK model for humans and to assess the reliability of the model in estimating plasma levels of xenobiotics, where these values are known from experimentation. In addition, we draw comparisons with alternative methods for predicting human pharmacokinetic properties that involve extrapolation from experimental data generated in animals.Just as there are numerous published compound-specific PBPK models for the rat that use data derived from in vivo studies (Sugita et al., 1982;Igari et al., 1983;Tsuji et al., 1983;Bernareggi and Rowland, 1991;Kawai et al., 1994;Blakey et al., 1997), there are many examples of comparable PBPK models for humans that rely upon scaling f...

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Pharmacokinetics and metabolism of dofetilide in mouse, rat, dog and man

Cited by 60 publications

References 11 publications

Paradoxical Effect of Dofetilide on Action Potential Duration and Calcium Transient Amplitude in Newborn Rabbit Ventricular Myocytes

Paradoxical Effect of Dofetilide on Action Potential Duration and Calcium Transient Amplitude in Newborn Rabbit Ventricular Myocytes

Dofetilide

Application of a Generic Physiologically Based Pharmacokinetic Model to the Estimation of Xenobiotic Levels in Human Plasma

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