Acetaminophen distribution in the rat central nervous system

Based on the evidence that the antinociceptive effects of acetaminophen cou ld be mediated centrally, tissue distribution of the drug after systemic ad ministration was determined in rat anterior and posterior cortex, striatum, hippocampus, hypothalamus, brain stem, ventral and dorsal spinal cord. In a first study, rats were treated with acetaminophen at 100, 200 or 400 mg/k g per os (p.o.), and drug levels were determined at 15, 45, 120, 240 min by high performance liquid chromatography (HPLC) coupled with electrochemical detection (ED). In a second study, 45 min after i.v. administration of [H- 3]acetaminophen (43 mu Ci/rat; 0.65 mug/kg), radioactivity was counted in t he same structures, plus the septum, the anterior raphe area and the cerebe llum. Both methods showed a homogeneous distribution of acetaminophen in al l structures studied. Using the HPLC-ED method, maximal distribution appear ed at 45 min. Tissue concentrations of acetaminophen then decreased rapidly except at the dose of 400 mg/kg where levels were still high 240 min after administration, probably because of the saturation of clearance mechanisms . Tissue levels increased with the dose up to 200 mg/kg and then leveled of f up to 400 mg/kg. Using the radioactive method, it was found that the tiss ue/blood ratio was remarkably constant throughout the CNS, ranking from 0.3 9 in the dorsal spinal cord to 0.46 in the cerebellum. These results, indic ative of a massive impregnation of all brain regions, are consistent with a central antinociceptive action of acetaminophen. (C) 2001 Elsevier Science . All rights reserved.