EXTRAHEPATIC GLUCURONIDATION OF PROPOFOL IN MAN - POSSIBLE CONTRIBUTION OF GUT WALL AND KIDNEY

Objective: Results from clinical pharmacokinetic studies of propofol i ndicate that this i.v. anaesthetic agent may undergo significant extra hepatic glucuronidation. We have investigated whether glucuronidation of propofol takes place in the kidney and/or the gut wall. First, prop ofol concentrations were measured in arterial (radial artery) and port al venous blood of 12 cirrhotic patients with trans internal-jugular p orto-systemic shunting (TIPSS). Results. In 7 of the 12 patients arter ial propofol concentrations were higher than portal venous concentrati ons. In the remaining patients, propofol concentrations were higher in the portal vein than the radial artery. Since an additional study in 5 patients anaesthetized with propofol while undergoing cholecystectom y showed propofol and an acid-labile conjugate of it in bile, it is di fficult to interpret the results in patients with TIPSS due to the pos sibility of enterohepatic cycling. Next, in vitro studies with human l iver (n = 5), kidney (n = 5) and small intestinal (n = 5) microsomes s howed that all three tissues were capable of forming propofol glucuron ide. V-max for propofol glucuronidation was approximately 3 to 3.5 tim es higher in kidney (5.56 nmol . min(-1). mg(-1) protein) than liver ( 1.80 nmol . min(-1). mg(-1) protein) and small intestine (1.61 nmol . min(-1). mg(-1) protein). Conclusion: Based on these in vitro results, it is concluded that extrahepatic glucuronidation in the small intest ine and especially in the kidney may contribute to the overall glucuro nidation of propofol in man.