Extrahepatic glucuronidation of propofol in man and rat
(1996)
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- Propofol is a rapidly acting general anesthetic which is widely used as an intravenous agent for both the induction and maintenance of anesthesia in children and in adult patients. Propofol is eliminated by metabolism and its blood clearance exceeds liver blood flow, thus indicating the existence of extrahepatic metabolism. Studies in patients during cardiopulmonary bypass surgery show that the lungs do not contribute to the extrahepatic metabolism of propofol. <BR> Th extrahepatic elimination of propofol with special emphasis on glucuronidation, a major biotransformation pathway of propofol in man and rat, was investigated in a series of experiments. First, it was shown that the elimination kinetics of porpofol were not affected in children with severe liver dysfunction due to biliary atresia, indicating indirectly that organs other than the liver (propably the small intestine and/or the kidneys) may be involved in the elimination of porpofol. Next, it was shown that propofom blood concentrations were lower in the hepatic portal vein as compared to the radial artery in 60% of patients studied who were undergoing trans internal jugular porto-systemic shunt. In the remaining patients, however, hepatic portal venous propofol concentrations were higher than radial arterial concentrations. This observation may be explained by enterohepatic circulation since the results of an additional study in five patients undergoing cholecystectomy showed the presence of porpofol and its glucuronide in the bile. In vitro studies, carried out with microsomes prepared from human small intestine, liver and kidney samples, demonstrated not only that all three organs were capable of glucuronidating propofol, but also that the maximum rate (Vmax) for this reaction was similar in the liver and small intestine and three times higher in the kidney. <BR> Finally, the contribution of the gastrointestinal tract, the liver and the lungs to the first-pass effect of propofol was studied in the rat. Following administration of propofol via intra-arterial, intravenous, hepatic portal venous and oral routes it was demonstrated that the intestine contributed most to the first-pass effect of propofol. In addition, in vitro studies showed that propofol readily crossed Caco-2 cell monolayers indicating that poor intestinal permeability is not an alternative explanation for the low oral bioavailability. <BR> In conclusion, the results of these studies show the existence of extrahepatic metabolism of propofol in man and rat. The small intestine and the kidneyx are the most probable sites of this extrahepatic metabolism. However, their exact contribution to the systemic clearance of propofol, in vivo, remains to be elucidated.
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Raoof, A. A. (1996). Extrahepatic glucuronidation of propofol in man and rat. https://hdl.handle.net/2078.5/111287