METABOLITE KINETICS - FORMATION OF ACETAMINOPHEN FROM DEUTERATED AND NON-DEUTERATED PHENACETIN AND ACETANILIDE ON ACETAMINOPHEN SULFATION KINETICS IN THE PERFUSED-RAT-LIVER PREPARATION

  • 1 January 1982
    • journal article
    • research article
    • Vol. 222  (1) , 14-19
Abstract
The role of hepatic intrinsic clearances for metabolite formation from various precursors on subsequent metabolite elimination was investigated in the once-through perfused rat liver preparation. Two pairs of acetaminophen precursors ([14C]phenacetin-d5 and [3H]phenacetin-d0, [14C]acetanilide and [3H]phenacetin) were delivered by constant flow (10 ml/min per liver) either by normal or retrograde perfusion to the rat liver preparations. The extents of acetaminophen sulfation were compared within the same preparation. The higher the hepatocellular activity (intrinsic clearance) for acetaminophen formation, the greater the extent of subsequent acetaminophen sulfation. The findings were explained on the basis of blood transit time and metabolite duration time. Because blood has only a finite transit time in liver, the longer the drug requires for metabolite formation, the less time will remain for metabolite formation, and the degree of subsequent sulfation will be lower. When the drug forms the primary metabolite rapidly, a longer time will remain for the metabolite to be sulfated in liver to result in a greater degree of metabolite sulfation. The effects of hepatic intrinsic clearances for metabolite formation and zonal distribution of enzyme systems for metabolite formation and elimination in liver are discussed.

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