Liver propafenone

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. 

Hepatic function impairment Propafenone is highly metabolized by the liver administer cautiously to patients with impaired hepatic function. The clearance of propafenone is reduced and the elimination half-life increased in patients with significant hepatic dysfunction. The dose of propafenone should be approximately 20% to 30% of the dose given to patients with normal hepatic function. 

WARNING Co administration w/ ritonavir assoc w/ Hep hepatic decomp w/ fatalities. D/C w/ S/Sxs of H Uses HIV 1 Infxn w/ highly Tx-experienced pts or HIV 1 strains resistant to multiple protease inhibitors. Must be used w/ ritonavir 200 mg Action Antiretroviral HIV-1 protease inhibitor Dose 500 mg PO bid w/ food, administer w/ ritonavir 200 mg PO bid Caution [C, -] Sulfa aU gy, Uvct Dz Contra Mod-severe hepatic insuff concomitant use w/ amiodarone, astemizole, bepridil, cisapride, ergots, flecainide, lovastatin, midazolam, pimozide, propafenone, quinidine, rifampin, simvastatin, terfenadine, triazolam, St. John s wort Disp Caps SE HA, GI distress, rash, fati e, fat redistribution, hyperglycemia, Hep, liver Dz, lipid elevations Interactions T Effects OF anticoagulants, antipits, azole antifun-... 

Propafenone has some structural similarities to propranolol and possesses weak 3-blocking activity. Its spectrum of action is very similar to that of quinidine, but it does not prolong the action potential. Its sodium channel-blocking kinetics are similar to that of flecainide. Propafenone is metabolized in the liver, with an average half-life of 5-7 hours. The usual daily dosage of propafenone is 450-900 mg in three divided doses. The drug is used primarily for supraventricular arrhythmias. The most common adverse effects are a metallic taste and constipation arrhythmia exacerbation can also occur. 

Propafenone can increase the serum activities of transaminases and other enzjmes associated with liver function... 

Mondardini A, Pasquino P, Bernard P, Aluffi E, Tartaglino B, Mazzucco G, Bonino F, Verme G, Negro F. Propafenone-induced liver injury report of a case and review of the hterature. Gastroenterology 1993 104(5) 1524-6. 

Beyond those in vivo examples depicted in Table 4, there are some in vitro data suggesting stereoselective drug interactions with oral anticoagulants. For example, Hermans and Thijssen [68] investigated the potential of metabolic interactions in vitro between warfarin or acenocou-marol and cimetidine, propafenone, sulphaphenazole, or omeprazole using human liver microsomes. Sulphaphenazole competitively inhibited the 7- and in some experiments the 6-hydroxylation of S-warfarin and R- and S-acenocoumarol. Omeprazole partly inhibited the 6- and 7-hydroxylation of R-warfarin, R-acenocoumarol, and S-acenocoumarol [68]. 

In humans, propafenone undergoes extensive metabolism ( 100% of the dose) with 5-hydroxy and N-dealkyl propafenone as the major metabolites [113]. Additionally, Kroemer et al. [113] demonstrated that only the 5-hydroxylation pathway of propafenone is associated with the debrisoquine hydroxylation phenotype. In vivo [85], the R(—) enantiomer of propafenone shows a higher clearance than its antipode in both extensive and poor metabolizers of debrisoquine, with the degree of stereoselectivity being almost the same in both populations. This suggests that the 5-hydroxylation of propafenone is not the reason behind the stereoselectivity in the metabolism of the drug. Indeed, in vitro studies [114,115] have shown that the intrinsic clearances of the enantiomers of propafenone for the hydroxylation pathway are very similar after the incubation of the racemate with human liver microsomes. It is also reported [115,116] that the other major metabolic pathway, N-dealkylation, is not stereoselective. Therefore it appears that the metabolic pathways other than 5-hydroxyla-tion and N-dealkylation are responsible for the stereoselectivity in the metabolism of propafenone observed in vivo. 

Hemeryck, A. De Vriendt, C. Belpaire, F.M. Effect of selective serotonin reuptake inhibitors on the oxidative metabolism of propafenone in vitro studies using human liver microsomes. J. Clin. Psychopharmacol. 2000, 20, 428 34. 

Mexiletine is also metabolised by CYP2D6 (e.g. see Mexiletine + Propafenone , p.269). In an in vitro study using human liver microsomes, paroxetine, fluoxetine, and sertraline extensively inhibited the metabolism of mexiletine. Using a model to prediet in vivo interactions, it was suggested that both fluoxetine and paroxetine may interact with mexiletine to a clinically relevant extent, whereas sertraline is less likely to interact. ... 

In a preliminary report of a study in 7 non-smoking subjects who were fast metabolisers of propafenone, phenobarbital 100 mg daily for 3 weeks reduced the levels of a single 300-mg dose of propafenone by 26 to 87% and the AUC by 10 to 89%. The intrinsic clearance inereased by 11 to 84%. The results in a further 4 heavy smokers were similar. These ehanges probably occur because phenobarbital (a potent stimulator of liver enzymes) increases the metabolism of the propafenone. The elinical importance of this awaits assessment, but check that propafenone remains effective if phenobarbital is added, and that toxicity does not occur if it is stopped. If the suggested mechanism is correct, other barbiturates would be expected to interact similarly. 

Quinidine inhibits the CYP2D6-dependent 5-hydroxylation of propafenone by the liver in those who are extensive metabolisers so that it is cleared more slowly. Its plasma levels are doubled as a result, but the overall antiarrhythmic effects remain effectively unchanged, possibly because the production of its active antiarrhythmic metabolite (5-hydroxypropafenone) is simultaneously halved. Quinidine increases the beta-bloctong effects of propafenone in extensive metabolisers because only the parent drug, and not the metabolites, has beta-blocking activity. ... 

It is suggested that propafenone reduees the metabolism of metoprolol and propranolol by the liver, thereby redueing their elearanee and raising serum levels. ... 

Information is limited but the interaetion would seem to be established. Concurrent use need not be avoided but antieipate the need to reduce the dosage of metoprolol and propranolol. Monitor closely because some patients may experience adverse effects. If the suggested mechanism of interaction is correct it is possible (but not confirmed) that other beta blockers that undergo liver metabolism will interact similarly but not those largely excreted unchanged in the urine. See Table 22.1 , (p.833) for the metabolism of some commonly used beta blockers. Also note that propafenone and the beta blockers have negative inotropic effects, which could be additive and result in unwanted cardiodepression. 

Uncertain. It has been suggested that propafenone may reduce the metabolism of theophylline by the liver, thereby increasing its levels. 

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