Glucuronidation of propofol and its analogs by human and rat liver microsomes.
Propofol (2,6-diisopropylphenol), widely used an intravenous anesthetic, is rapidly metabolized to its glucuronide in the in vivo studies. Kinetic parameters for the glucuronidation of propofol and its analogs, such as 2,5-diisopropylphenol, 2-tert-butyl-6-methylphenol, 2-tert-butyl-5-methylphenol, 2,6-dimethylphenol and 2,5-dimethylphenol, were determined in vitro using human and rat liver microsomes. 2,5-Dimethylphenol and 2-tert-butyl-6-methylphenol exhibited the highest and lowest glucuronidation rates, respectively. Substitutes at the 2,6-positions gave lower glucuronidation rates than those at the 2,5-positions in both the human and rat microsomes. 2,5-Diisopropylphenol was glucuronidated at a lower rate in human than propofol. The affinity of uridine 5'-diphosphate (UDP)-glucuronosyltransferase for disubstituted phenols, such as propofol, 2,5-diisopropylphenol, 2,5-dimethylphenol, and 2-tert-butyl-6-methylphenol, gave higher Km values in human liver microsomes than in rat ones, and lower Vmax values showed similar relationship, expect for Vmax in propofol. The alkyl group at the 6 position showed a higher Km for glucuronidation by a steric hindrance in the human and rat microsomes. Our results propose that the glucuronidation of propofol and its analogs may not be explained by only a steric hindrance.
Shimizu
Makiko
M
Department of Clinical Pharmacology and Toxicology, Showa Pharmaceutical University, Tokyo, Japan. shimizu@ac.shoyaku.ac.jp
Matsumoto
Yoshiaki
Y
Tatsuno
Masahiro
M
Fukuoka
Masamichi
M
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D020719:Glucuronides / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D015742:Propofol / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar
D020719:Glucuronides; D015742:Propofol