Propafenone metabolism

Inselmann G, Volkmann A, Heidemann H. Comparison of the effects of liposomal amphotericin B and conventional amphotericin B on propafenone metabolism and cytochrome P450 in rats. Antimicrob Agents Chemother 2000 44 131. 

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. 

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. 

Quinidine has been added to propafenone with the intention of inhibiting propafenone metabolism via CYP2D6 in the hope of improving outcome (8). Of 60 patients with paroxysmal atrial fibrillation given propafenone 300-450 mg/day for 8 weeks there were 19 refractory cases, who were then randomized double-blind to receive either a higher dose of propafenone (450-675 mg/day) or the standard dose of propafenone with extra low-dose quinidine (150 mg/day), each for 8 weeks, with subsequent crossover to the alternative. Patients who even then were not adequately controlled were given the standard dose of propafenone plus a standard dose of quinidine (600 mg/day) for a further 8 weeks. The plasma propafenone concentrations during the four phases were as follows ... 

FanC, Tang M,LauC-P, Chow M The effect of quinidine on propafenone metabolism in Chinese patients. ClinInvestMed( 99%) (Suppl) S12. 

A 46-year-old man developed syncope, a widen QRS interval, and depressed left ventricular systolic function while taking propafenone 425 bd for atrial fibrillation. This may have been due to an increased dosage of propafenone combined with heavy alcohol consumption, possibly associated with genetic susceptibility to inhibition of propafenone metabolism by alcohol. 

Others later commented that since propafenone and carvedilol are both metabolized by CYP2D6, inhibition of propafenone metabolism by carvedilol may have caused the syncope reported in this case [8 ]. 

About 97% of po dose is absorbed from the GI tract. The dmg undergoes extensive first-pass hepatic metaboHsm and only 12% of the po dose is bioavailable. More than 95% is protein bound and peak plasma concentrations are achieved in 2—3 h. Therapeutic plasma concentrations are 0.064—1.044 lg/mL. The dmg is metabolized in the Hver to 5-hyroxypropafenone, which has some antiarrhythmic activity, and to inactive hydroxymethoxy propafenone, glucuronides, and sulfate conjugates. Less than 1% of the po dose is excreted by the kidney unchanged. The elimination half-life is 2—12 h (32). 

Dilger, K., Greiner, B., Fromm, M.F., Flofmann, U., Kroemer, H.K. and Eichelbaum, M. (1999) Consequences of rifampicin treatment on propafenone disposition in extensive and poor metabolizers of CYP2 D6. Pharmacogenetics, 9, 551-559. 

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. 

Drugs that may be affected by duloxetine include drugs extensively metabolized by CYP2D6 (eg, flecainide, phenothiazines, propafenone, tricyclic antidepressants, thioridazine), alcohol, CNS-acting drugs, MAOIs, and drugs highly bound to plasma proteins (eg, warfarin). 

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 Orally active, weak B-blocking activity supraventricular arrhythmias hepatic metabolism ... 

Lopinavir/Ritonavir (Kaletra) [Anrirelroviral/Protease Inhibitor] Uses HIV Infxn Action Protease inhibitor Dose Adults. Tx naive 2 tab PO daily or 1 tab PO bid Tx experiencedpt 1 tab PO bid (T dose if w/ amprenavir, efavirenz, fosamprenavir, nelfinavir, nevirapine) Peds. 7-15 kg 12/3 mg/kg PO bid 15-40 kg 10/2.5 mg/kg PO bid >40 kg Adult dose w/ food Caution [C, /-] Numerous interactions Contra w/drugs dependent on CYP3A/CYP2D6 (Table VI-8) Disp Tab, soln SE Avoid disulfiram (soln has EtOH), metronidazole GI upset, asthenia, T cholesterol/triglycerides, pancreatitis protease metabolic synd Interactions T Effects Wl clarithromycin, erythromycin T effects OF amiodarone, amprenavir, azole andfungals, bepridil, cisapride, cyclosporine, CCBs, ergot alkaloids, flecainide, flurazepam, HMG-CoA reductase inhibitors, indinavir, lidocaine, meperidine, midazolam, pimozide, propafenone, propoxyphene, quinidine, rifabutin, saquinavir, sildenafil, tacrolimus, terfenadine, triazolam, zolpidem 1 effects Wl barbiturates, carbamazepine, dexamethasone, didanosine, efavirenz, nevirapine, phenytoin, rifabutin, rifampin, St. John s wort 1 effects OF OCPs, warfarin EMS Use andarrhythmics and benzodiazepines... 

Lee JT, Kroemer HK, Silberstein DJ, Funck-Brentano C, Lineberry MD, Wood AJ, Roden DM, Woosley RL. The role of genetically determined polymorphic drug metabolism in the beta-blockade produced by propafenone. N Engl J Med 1990 322 1764-1768. 

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). 

The metabolism of propafenone is complex. The primary pathway involves CYP2D6, with some people having higher activity than others those with less extensive activity are more susceptible to the effects of CYP2D6 inhibitors. CYP3A4 acts as a back-up pathway. 

MEXILETINE PROPAFENONE t serum levels of mexiletine Propafenone inhibits CYP2D6-mediated metabolism of mexiletine no case reports of adverse clinical effects but is potential for proarrhythmias Monitor ECG closely... 

PROPAFENONE I. ANTIARRHYTHMICS - disopyra-mide, procainamide 2. ANTIBIOTICS - macrolides (especially azithromycin, clarithromycin, parenteral erythromycin, telithromycin), quinolones (especially moxifloxacin), quinupristin/ dalfopristin 3. ANTICANCER AND IMMUNOMODULATING DRUGS -arsenic trioxide 4. ANTIDEPRESSANTS - TCAs, venlafaxine 5. ANTIEMETICS-dolasetron 6. ANTIFUNGALS-fluconazole, posaconazole, voriconazole 7. ANTIHISTAMINES - terfenadine, hydroxyzine, mizolastine 8. ANTI-M ALARIALS - artemether with lumefantrine, chloroquine, hydroxychloroquine, mefloquine, quinine 9. ANTIPROTOZOALS - pentamidine isetionate 10. ANTIPSYCHOTICS-atypicals, phenothiazines, pimozide II. BETA-BLOCKERS - sotalol 12. BRONCHODILATORS -parenteral bronchodilators 13. CNS STIMULANTS - atomoxetine Risk of ventricular arrhythmias, particularly torsades de pointes Additive effect these drugs prolong the Q-T interval. Also, amitriptyline, clomipramine and desipramine levels may be t by propafenone. Amitriptyline and clomipramine may t propafenone levels. Propafenone and these TCAs inhibit CYP2D6-mediated metabolism of each other Avoid co-administration... 

PROPAFENONE NS AIDS Serum levels of propafenone may be t by parecoxib Parecoxib is a weak inhibitor of CYP2D6-mediated metabolism of propafenone Monitor PR and BP closely. If possible, use only short courses of NS AID... 

PROPAFENONE OPIOIDS Methadone may t propafenone levels Methadone inhibits CYP2D6-mediated metabolism of propafenone Monitor PR and BP closely... 

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