title: In vitro glucuronidation of propofol in microsomal fractions from human liver, intestine and kidney: tissue distribution and physiological role of UGT1A9.
abstract: Propofol (2,6-diisopropylphenol) is intravenously administered for anesthetic induction and maintenance, and is rapidly metabolized into its glucuronide, mainly by UDP-glucuronosyltransferase 1A9 (UGT1A9). In this study, propofol glucuronidation by liver microsomes (HLM), intestinal microsomes (HIM) and kidney microsomes (HKM) of humans were examined. The expression of UGT1A9 protein in HLM, HIM and HKM was analyzed by immunoblotting. The staining band intensities for UGT1A9 of HIM and HKM were 12% and 119% those of HLM, respectively. The kinetics of propofol glucuronidation by HLM and HKM exhibited substrate inhibition, whereas the kinetics by HIM followed the Michaelis-Menten model. The K(m), V(max) and CL(int) values of HLM were 41.8 μM, 5.21 nmol/min/mg protein and 126 μl/min/mg protein, respectively. The K(m) value of HIM was significantly higher (6.7-fold) than that of HLM, and the V(max) and CL(int) values were significantly lower (56% and 8.3%, respectively) than those of HLM. The K(m) value of HKM was comparable to that of HLM, and the V(max) and CL(int) values were significantly higher (2.1- and 3.7-fold, respectively) than those of HLM, respectively. These findings suggest that UGT1A9 expressed in the kidney as well as in the liver plays an important role in propofol glucuronidation. The information gained in this study should contribute to an appropriate use of drugs metabolized by UGT1A9.
authors.forename: M
authors.initials: M
authors.lastname: Mukai
authors.forename: S
authors.initials: S
authors.lastname: Tanaka
authors.forename: K
authors.initials: K
authors.lastname: Yamamoto
authors.forename: M
authors.initials: M
authors.lastname: Murata
authors.forename: K
authors.initials: K
authors.lastname: Okada
authors.forename: T
authors.initials: T
authors.lastname: Isobe
authors.forename: M
authors.initials: M
authors.lastname: Shigeyama
authors.forename: H
authors.initials: H
authors.lastname: Hichiya
authors.forename: N
authors.initials: N
authors.lastname: Hanioka
mesh_terms: D018686:Anesthetics, Intravenous / Q000378:metabolism* / Q000493:pharmacokinetics; D020719:Glucuronides / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008861:Microsomes / Q000378:metabolism*; D008862:Microsomes, Liver; D015742:Propofol / Q000378:metabolism* / Q000493:pharmacokinetics; D014018:Tissue Distribution; D000090264:UDP-Glucuronosyltransferase 1A9
chemical_list: D018686:Anesthetics, Intravenous; D020719:Glucuronides; C000715591:UGT1A9 protein, human; D014453:Glucuronosyltransferase; D000090264:UDP-Glucuronosyltransferase 1A9; D015742:Propofol