Several drugs show saturable metabolism during their """"""""first-pass"""""""" through intenstine and liver. As a consequence, the bioavailability of these drugs increases with increasing dose. The requirements for oral dosing of these drugs can vary strickingly within and between normal subjects and even more strikingly in patients with diseases that alter gastrointestinal or hepatic physiology. Although saturable first-pass metabolism raises important problems in therapeutics, the fundamental knowledge of the pharmacokinetics of the process in vivo is limited. The individual contributions of the two metabolizing organs, intestine and liver, is unknown. These gaps in knowledge have arisen because the """"""""in series"""""""" anatomic arrangement of the intestine and liver hamper study of each organ separately. We have adapted the procedure of surgical construction of a portacaval tranposition in the dog to allow examination of saturable first-pass metabolism of propranolol separately in liver and intestine. Following portacaval transposition, injection of drug into a hindlimb allows the total dose to bypass the intestinal and be delivered directly to the liver. An oral dose enters the systemic circulation after only traversing the intestine. We now plan to study salicylamide, an intriguing drug because of the significant contribution of both intestine and liver to its saturable first-pass metabolism. We will examine the influence of dose, rate of delivery, sulfate and glucuronide precursors, protein binding, enzyme activity, and liver blood flow on its saturable metabolism. We will seek the relationships between the physiologic variables and hepatic clearance of salicylamide. We will compare the observed changes in clearance under a variety of conditions with those predicted by the two commonly-used mathematical models of hepatic drug clearance by the liver.
