PT  - JOURNAL ARTICLE
AU  - K S Pang
AU  - L Waller
AU  - M G Horning
AU  - K K Chan
TI  - Metabolite kinetics: formation of acetaminophen from deuterated and nondeuterated phenacetin and acetanilide on acetaminophen sulfation kinetics in the perfused rat liver preparation.
DP  - 1982 Jul 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 14--19
VI  - 222
IP  - 1
4099  - http://jpet.aspetjournals.org/content/222/1/14.short
4100  - http://jpet.aspetjournals.org/content/222/1/14.full
SO  - J Pharmacol Exp Ther1982 Jul 01; 222
AB  - The role of hepatic intrinsic clearance for metabolite formation from various precursors on subsequent metabolite elimination was was investigated in the once-through perfused rat liver preparation. Two pairs of acetaminophen precursors: [14C] phenacetin-d5 and [3H] phenacetin-do, [14C] acetanilide and [3H] phenacetin were delivered by constant flow (10 ml/min/liver) either by normal or retrograde perfusion to the rat liver preparations. The extents of acetaminophen sulfation were compared within the same preparation. The data showed that 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 of blood having only a finite transit time in liver, the longer the drug requires for metabolite formation, the less time will remain for metabolite sulfation and the less will be the degree of subsequent sulfation. Conversely, 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. Finally, the effects of hepatic intrinsic clearances for metabolite formation and zonal distribution of enzyme systems for metabolite formation and elimination in liver are discussed.