The oral route remains the most common, convenient, economical, and generally safest means for drug administration. However, for drugs intended to act systemically, this route is not always the most efficient due to the numerous anatomic and physiologic barriers that drugs can encounter from the time of ingestion until the time of entry into the general circulation. Consequently, before an orally administered drug enters the systemic circulation and elicits pharmacologic effects in the target tissue(s), significant loss of the original dose can occur during sequential passage through the gastrointestinal (GI) tract, the liver, and the cardiopulmonary system. These barriers can preclude the use of some drugs as oral agents. Isoproterenol, dihydroergotamine, lidocaine, nitroglycerin, fentanyl, and naloxone are examples of drugs that are susceptible to a high first-pass effect, which refers to the loss of drug as the dose passes, for the first time, through organs of elimination during transit from the site of administration to the systemic circulation [1]. Processes known to cause significant loss of active drug during first-pass include incomplete release from the dosage form, degradation in the GI lumen, poor permeation through the GI wall, active export into the GI lumen, biliary excretion, and metabolism. Of these processes, only metabolism can take place in all of the aforementioned organs.