Propafenone pharmacokinetics

Absorption/Distribution - Propafenone is nearly completely absorbed after oral administration with peak plasma levels occurring approximately 3.5 hours after administration. It exhibits extensive first-pass metabolism resulting in a dose-dependent and dosage-form-dependent absolute bioavailability. Propafenone follows a nonlinear pharmacokinetic disposition presumably due to saturation of first-pass hepatic metabolism as the liver is exposed to higher concentrations of propafenone and shows a very high degree of interindividual variability. 

Metabolism/Excretion - There are 2 genetically determined patterns of propafenone metabolism. In more than 90% of patients, the drug is rapidly and extensively metabolized with an elimination half-life of 2 to 10 hours. These patients metabolize propafenone into two active metabolites 5-hydroxypropafenone and N-depropylpropafenone. They both are usually present in concentrations less than 20% of propafenone. The saturable hydroxylation pathway is responsible for the nonlinear pharmacokinetic disposition. 

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. 

Siddoway LA, Thompson KAMKT, McAllister CB, Wang T, Wilkinson GR, Roden DM, Woosley RL. Polymorphism of propafenone metabolism and disposition in man clinical and pharmacokinetic consequences. Circulation 1987 75 785-791. 

Inhibition of cytochrome P450 isoenzymes (e.g., nonlinear pharmacokinetics of propafenone, producing an exponential increase of plasma levels due to inhibition of its metabolism by CYP2D6, after application of higher doses). 

Cardaioh P, Compostella L, De Domenico R, Papalia D, Zeppehiiu R, Libardoni M, Pulido E, Cucchini F. Influenza del propafenone sulla farmacocinetica della digossina somministrata per via orale studio su volontari sani. [Effect of propafenone on the pharmacokinetics of digoxin administered orally a study in healthy volunteers.] G Ital Cardiol 1986 16(3) 237-A0. 

Ujhelyi MR, O Rangers EA, Fan C, Kluger J, Pharand C, Chow MS. The pharmacokinetic and pharmacodynamic interaction between propafenone and lidocaine. Clin Pharmacol Ther I993 53(I) 38-48. 

Labbe L, O Hara G, Lefebvre M, Lessard E, Gilbert M, Adedoyin A, Champagne J, Hamelin B, Turgeon J. Pharmacokinetic and pharmacodynamic interaction between mexiletine and propafenone in human beings. Clin Pharmacol Ther 2000 68(l) 44-57. 

Bryson HM, Palmer KJ, Langtry HD, Fitton A. Propafenone. A reappraisal of its pharmacology, pharmacokinetics and therapeutic use in cardiac arrhythmias. Drugs 1993 45(1) 85-130. 

Dilger K, Hofmann U, Klotz U. Enzyme induction in the elderly effect of rifampin on the pharmacokinetics and pharmacodynamics of propafenone. Clin Pharmacol Ther 2000 67 512-520. 

In more recent studies, Turgeon and colleagues have reported the effects of coadministration of caffeine [131] or propafenone [132] on the stereoselective pharmacokinetics of mexiletine in poor and extensive metabolizers of debrisoquine. Caffeine, a substrate for CYP1A2, did not significantly change the plasma eoncentrations of mexiletine enantiomers in either PMs or EMs [131]. However, it resulted in a slight decrease ( 15%) in the urinary recovery of N-hydroxymexiletine generated from the R enantiomer in both EMs and PMs [131]. The metabolism of the S enantiomer was not affected because the N-hydroxymexiletine recovered in urine is mostly from the R enantiomer. 

In contrast to caffeine, propafenone coadministration significantly reduced the metabolism of both enantiomers of mexiletine in EMs [132]. However, it did not have a significant effect on the pharmacokinetics of mexiletine enantiomers in PMs. In fact, after coadministration of propafenone to EMs, the plasma concentration-time profiles and pharmacokinetics of mexiletine enantiomers in these subjects were not distinguishable from those in PMs [132]. These results are in agreement with the inhibitory effects of propafenone on the CYP2D6 pathway and are similar to those obtained with quinidine, another CYP2D6 inhibitor (Table 13). 

The pharmacokinetics of propafenone enantiomers are summarized in Table 14. The first study on the stereoselective pharmacokinetics of propafenone [84] reported the pharmacokinetics of the individual enantiomers in healthy male volunteers after the oral administrations of the enantiomers separately. Six of the seven volunteers were characterized as EMs and one as PM. The enantiomeric AUCs in the PM subject were > ten times higher than the average value in EMs. Additionally, whereas the oral clearances of the enantiomers were close in the PM subject, the oral clearance of S-propafenone was on average > twice than that of R-propafenone in EMs, resulting in higher plasma concentrations of R-propafenone in EMs... 

Table 14 Stereoselective Pharmacokinetics (MeaniSD) of Oral Propafenone After the Administration of the Individual Enantiomers (R or S) or the Racemate (RS)... 

The pharmacokinetic interaction of the two enantiomers of propafenone also has some pharmacodynamic ramifications. Kroemer et al. [85] showed that the beta-blocking effect of 150 mg of the racemate was more intense than that of 75 mg of the S enantiomer administered alone. This apparent discrepancy could be explained by their finding of lower clearance and higher plasma concentrations of S enantiomer in the presence of its antipode (Table 14). These data clearly show that the pharmacological activities of racemates cannot be simply assumed to be a summation of the effects of the individual enantiomers. 

The enantiomer-enantiomer interaction observed for propafenone in Caucasians (Table 14) was also found in Chinese subjects [134]. The oral clearance of S-propafenone was reduced to one-half when it was administered as a racemate as opposed to pure enantiomer administration [134]. Additionally, CYP2D6-dependent variability in the pharmacokinetics of propafenone reported in Caucasians (Table 14) was also observed in Chinese subjects [135]. These data suggest that the stereoselective... 

Collectively, these data indicate that the stereoselective pharmacokinetics and pharmacodynamics of propafenone are influenced by the debrisoquine phenotype of the patient and the interaction between the two enantiomers. It is not surprising that the pharmacokinetics of the drug are highly variable (Table 14). 

Brode, E. Muller-Peltzer, H. Hollmann, M. Comparative pharmacokinetics and clinical pharmacology of propafenone enantiomers after oral administration to man. Methods Find Exp. Clin. Pharmacol. 1988, 10, 717-727. 

Chen, X. Zhong, D. Blume, H. Stereoselective pharmacokinetics of propafenone and its major metabolites in healthy Chinese volunteers. Eur. J. Pharm. Sci. 2000, 10, 11-16. 

Propafenone has minimal effects on the pharmacokinetics of intravenous lidocaine, but the severity and duration of the CNS adverse effects of lidocaine are increased. 

Chan GL-Y, Axelson JE, Kerr CR. The effect of phenobarbital on the pharmacokinetics of propafenone inman. PharmRes ( 9Z S) 5, S153. 

A study in 12 healthy subjects (10 extensive metabolisers and 2 poor metabolisers of propafenone) given propafenone 225 mg every 8 hours found that the eoncurrent use of cimetidine 400 mg every 8 hours eaused some ehanges in the pharmacokinetics and pharmacodynamics of the propafenone, with wide intersubject variability. Raised mean peak and steady-state plasma levels were seen (24 and 22%, respectively), but these did not reach statistical significance. A slight increase in the QRS duration also occurred. However, none of the changes were considered clinically important. 

Pritchett ELC, Smith WM, Kirsten EB. Pharmacokinetic and pharmacodynamic interactions of propafenone and cimetidine. J Clin Pharmacol (1988) 28, 619-24,... 

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