Flecainide pharmacokinetics

D6 - Tolterodine is not expected to influence the pharmacokinetics of drugs that are metabolized by cytochrome P450 2D6, such as flecainide, vinblastine, carbamazepine, and tricyclic antidepressants. 

The pharmacokinetics of saquinavir is modified by agents that alter isoenzyme CYP3A4 of the cytochrome P-450 system and P-glycoprotein transporter. It should not be administered with midazolam, triazolam and ergot derivatives. The plasma concentrations of saquinavir are lower when coadministered with efavirenz, nevirapine or rifampin. Ritonavir reverses the effects of nevirapine on saquinavir. The coadministration of astemizole, terfenadine, amiodarone, bepridil, quinidine, propafenone or flecainide with saquinavir is also not recommended due to its potential for serious and/or life-threatening reactions. 

Pharmacokinetics Flecainide is absorbed orally, undergoes minimal biotransfbrmation, and has a half-life of 16 to 20 hours. 

The potency of enantioselective gas chromatography became apparent in the pharmacokinetic studies of flecainide [3] and two of its chiral metabolites as carried out by Fischer et al. (40). Trace amounts of these compounds in plasma samples were screened for enantiomeric discrimination. 

Tjandra-Maga TB, van Hecken A, van Melle P, Verbesselt R, de Schepper PJ. Altered pharmacokinetics of oral flecainide by cimetidine. Br J Clin Pharmacol 1986 22(1) 108-10. 

Despite an early report that flecainide might alter the pharmacokinetics of digoxin, this action is minimal and probably of no clinical significance (72). The combination canses a significant increase in the PR interval but the clinical significance of this is unclear, it may be important for patients with impaired sinus node function (73). 

Williams AJ, McQuinn RL, Walls J. Pharmacokinetics of flecainide acetate in patients with severe renal impairment. Clin Pharmacol Ther 1988 43(4) 449-55. 

McQuinn RL, Pentikainen PJ, Chang SF, Conard GJ. Pharmacokinetics of flecainide in patients with cirrhosis of the liver. Chn Pharmacol Ther 1988 44(5) 566-72. 

Holtzman JL, Finley D, Mottonen L, Berry DA, Ekholm BP, Kvam DC, McQuinn RL, Miller AM. The pharmacodynamic and pharmacokinetic interaction between single doses of flecainide acetate and verapamil effects on cardiac function and drug clearance. Clin Pharmacol Ther 1989 46(l) 26-32. 

Neff C A, Davis L E, Baggot J D 1972 A comparative study of the pharmacokinetics of quinidine. American Journal of Veterinary Research 33 1521-1525 Ohmura H, Nukada T, Mizuno Y et al 2000 Safe and efficacious dosage of flecainide acetate for treating equine atrial fibrillation. Journal of Veterinary Medical Science 62 711-715... 

Ohmura H, Hiraga A, Aida H et al 2001 Determination of oral dosage and pharmacokinetic analysis of flecainide in horses. Journal of Veterinary Medical Science 63 511-514... 

The pharmacodynamics and pharmacokinetics of ( )-flecainide acetate have been studied extensively in animal models and in humans. This drug exhibits potent antiarrhythmic effects... 

There are comparatively few reports concerned with the stereoselective pharmacodynamics and pharmacokinetics of flecainide enantiomers. In vivo studies have revealed equipotency and equiactivity for the two enantiomers in mouse and dog models of arrhythmia. In vitro tests on canine Purkinje fibres have also shown that the enantiomers have comparable electrophysiologic activities. The two enantiomers have also shown similar affinities to a receptor site associated with cardiac sodium channels in isolated rat cardiac myocytes. ... 

The pharmacokinetic patterns of the enantiomers following oral administration in humans appear to be essentially parallel. The plasma R/S ratio seems to range from 0.67-1.44 in different patient populations 3,56,59. stereoselective elimination has been suggested in healthy subjects, which have been classified as poor metabolizers of the sparteine debrisoquine type R-flecainide is predominant in plasma after oral administration of the racemate. The oral AUCs of the enantiomers as well as the elimination half-lives were slightly, but significantly, different. This has been interpreted as being the result of stereoselective hepatic metabolism17. 

Table 12 Stereoselective Pharmacokinetics (Mean SD) of Oral Flecainide After the Administration of the Racemate to Extensive and Poor Metabolizers of Debrisoquine... 

Two earlier studies in patients and healthy subjects had found that the pharmacokinetics of flecainide and verapamil were only minimally affected by concurrent use, but the PR interval was increased by both drugs and additive depressant effects were seen on heart contractility and AV conduction. No serious adverse responses occurred. 

Flecainide and verapamil have little or no effects on the pharmacokinetics of each other, but they can apparently have additive depressant effects on the heart (negative inotropic and chronotropic) in both patients and healthy subjects. Verapamil alone and flecainide alone have been responsible for asystole and cardiogenic shock in a few patients. In the cases cited above " the cardiac depressant effects were particularly serious because the patients already had compromised cardiac function. 

Tsao YY, Gugger JJ. Delirium in a patient with toxic flecainide plasma concentrations the role of a pharmacokinetic drug interaction with paroxetine. Ann Pharmacother 2009 43(7) 1366-9. 

The effects of CYP2D6 genetic polymorphisms on the pharmacokinetics of a single oral dose of flecainide and on the extent of its interaction with paroxetine have been investigated in an open study in 21 healthy Korean volunteers [69 ]. The AUC, terminal half-life, and mean residence time increased significantly after paroxetine in those with the CYP2D6 10 allele, which is common among Asians. 

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