TY - JOUR T1 - First-pass metabolism of salicylamide. Studies in the once-through vascularly perfused rat intestine-liver preparation. JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 556 LP - 563 VL - 17 IS - 5 AU - X Xu AU - H Hirayama AU - K S Pang Y1 - 1989/09/01 UR - http://dmd.aspetjournals.org/content/17/5/556.abstract N2 - Salicylamide (SAM) metabolism was studied in a once-through in situ perfused rat intestine-liver preparation in a manner which mimicked the first-pass effect. SAM (40 or 200 microM) was delivered into the intestine via the superior mesenteric artery at a flow rate of 7.5 ml/min. The intestine venous outflow into the portal vein and the hepatic arterial flow (2.5 ml/min; without drug) served as dual inflows into the liver. The steady state intestinal and hepatic extraction ratios were 0.262 +/- 0.055 and 0.992 +/- 0.014, respectively, at 40 microM, and 0.206 +/- 0.035 and 0.638 +/- 0.117, respectively, at 200 microM. SAM glucuronide was found to be the only metabolite formed by the intestine at both doses. Less than 3% of the dose was secreted into the intestinal lumen, with SAM glucuronide and SAM as the major and minor components, respectively. Hepatic metabolism of SAM, however, revealed SAM sulfation as the predominant pathway, while glucuronidation and hydroxylation were minor metabolic pathways. About 6% of the dose was excreted into bile, mostly as SAM and gentisamide glucuronides. The interrelationship between the intestine and liver clearances was also examined by mass balance considerations and simulation of data. The total rate of elimination of substrate across the two organs is the sum of the rates of metabolism by each organ. However, the overall effective extraction ratio and, hence, the clearance, are less than the sum of the individual extraction ratios and organ clearances, respectively. Our results showed that intestinal metabolism regulated the available substrate for hepatic elimination, and hence modified the contribution of hepatic metabolism in the overall first-pass effect.(ABSTRACT TRUNCATED AT 250 WORDS) ER -