SULFATION OF ACETAMINOPHEN BY THE PERFUSED-RAT-LIVER - THE EFFECT OF RED-BLOOD-CELL CARRIAGE

Acetaminophen uptake and conversion in the perfused rat liver to aceta minophen sulfate was studied with the multiple indicator dilution tech nique (MID). Because acetaminophen is avidly bound to red blood cells and not albumin, a pre-equilibrated MID dose containing the nonelimina ted references (Cr-51-labeled red blood cells [RBC, a vascular referen ce], [Co-58]EDTA [a small molecular weight interstitial reference that does not enter cells], and D2O [a cellular reference]) and [H-3]-acet aminophen was introduced into the portal vein of the single-pass perfu sed rat liver (1 mg/L acetaminophen) under varying conditions of hemat ocrit, with observation of timed outflow profiles in the hepatic venou s blood. The [H-3]acetaminophen curve exhibited an early high peak, pa ralleling that for red cells and varying with hematocrit, followed by a prolonged decline, with the late appearance of acetaminophen sulfate product; the early peak disappeared when red cells were absent from t he dose and perfusate. Analysis demonstrated a slow release of acetami nophen from the red blood cells and rapid liver cell entry, so that re d cell binding was displayed as a red cell carriage effect that reduce d the rate of liver cell entry and hence of sulfation of [H-3]acetamin ophen. The liver cells exhibited a concomitant very low permeability t o product acetaminophen sulfate, leading to protracted product outflow curves. An inferred slow efflux-mediated storage phenomenon for produ ct was found to evolve as a result.