Effect of Diethylether on the Formation of Paracetamol Sulphate and Glucuronide in Isolated Rat Hepatocytes

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Abstract
Diethylether [an anesthetic] previously inhibited several pathways of drug metabolism, including conjugation of paracetamol in isolated rat hepatocytes. Since overall paracetamol conjugation consists of pathways of different subcellular localization (cytosolar sulfation and microsomal glucuronidation), the response of both pathways to diethylether was tested. The elimination of paracetamol (160 .mu.mol/l, initial concentration) and the formation of paracetamol sulfate and glucuronide were measured (high-performance liquid chromatography) in suspensions of isolated rat hepatocytes from fasted and fed animals over 1 h in the absence and presence of diethylether (30 mmol/l). Approximately 90% of the paracetamol elimination was by sulfation and nearly 10% by glucuronidation both in the controls and in the presence of ether. The overall disposition of paracetamol and the formation of sulfate were both reduced by about 50% in the presence of ether compared to the controls while the formation of glucuronide was reduced by 70%. The results were not influenced by the nutritional state of the animals before sacrifice. The inhibitory effect of ether on total paracetamol metabolism was mainly caused by reduced sulfation. Since microsomal glucuronidation was also inhibited by ether, both cytosolar and microsomal enzyme systems were sensitive to diethylether.