Assessment of Presystemic and Systemic Intestinal Availability of Orally Administered Drugs Using In Vitro and In Vivo Data in Humans: Intestinal Sulfation Metabolism Impacts Presystemic Availability Much More Than Systemic Availability of Salbutamol, SUL

Although hepatic availability has been extensively studied to assess the oral bioavailability of drugs, intestinal availability has not, especially that related to conjugative metabolism (phase II metabolism). The present study assessed intestinal presystemic availability by integrating the reported metabolism data in vitro and in vivo of salbutamol, SULT1A3 substrate, in humans. Intrinsic clearance from each organ was calculated with the reported kinetic parameters for salbutamol sulfation metabolism in vitro. Then, presystemic (except intestine) and systemic organ availability and organ clearance were estimated by scaling up the in vitro data using biochemical and physiological data. Scaling factors used were one third, one and three times. Intestinal presystemic availability was calculated without assumptions of a well‐stirred model. Presystemic availability of the intestine is much lower than systemic availability of the intestine. In addition, presystemic availability of the intestine is lower than presystemic availability of other organs, the liver or lung. SULT1A3 is expressed primarily in the intestine; therefore, it should be noted that intestinal metabolism affects the oral bioavailability of drugs, which are metabolized by SULT1A3. © 2008 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci