The biotransformation (or metabolism) of most antiarrhythmic drugs occurs in the liver and is mediated by cytochrome P-450 isoenzymes, of which P4502D6 and P4503A4 are 2 of the most important. However, some rapidly eliminated drugs are also metabolized in the plasma, blood cells, vascular endothelium, and lungs. Antiarrhythmic drugs such as amiodarone (99%), propafenone (90%), and verapamil (90%) are almost completely metabolized, whereas drugs such as tocainide (10%), procainamide (15%), bretylium tosylate (<10%), and D,L-sotalol (0%) are not. A number of antiarrhythmic drugs undergo extensive first-pass metabolism, which affects the dosage and route of administration. Lidocaine, for example, requires intravenous administration because of its extremely poor systemic bioavailability when taken orally, whereas propafenone, metoprolol tartrate, propranolol, and verapamil must be given in doses that are sufficiently high to compensate for their extensive first-pass metabolism.