title: Species and sex differences in propofol glucuronidation in liver microsomes of humans, monkeys, rats and mice.
abstract: Propofol (2,6-diisopropylphenol) is a short-acting anesthetic commonly used in clinical practice, and is rapidly metabolized into glucuronide by UDP-glucuronosyltransferase (UGT). In the present study, propofol glucuronidation was examined in the liver microsomes of male and female humans, monkeys, rats, and mice. The kinetics of propofol glucuronidation by liver microsomes fit the substrate inhibition model for humans and mice, the Hill model for monkeys, and the isoenzyme (biphasic) model for rats. The K(m), V(max), and CL(int) values of human liver microsomes were 50 μM, 5.6 nmol/min/mg protein, and 110 μL/min/mg protein, respectively, for males, and 46 μM, 6.0 nmol/min/mg protein, and 130 μL/min/mg protein, respectively, for females. The rank order of the CL(int) or CL(max) (in vitro clearance) values of liver microsomes was mice humans > monkeys > rats (high-affinity phase) rats (low-affinity phase) in both males and females. Although no significant sex differences were observed in the values of kinetic parameters in any animal species, the in vitro clearance values of liver microsomes were males < females in humans, males = females in rats (low-affinity phase), and males > females in monkeys, rats (high-affinity phase), and mice. These results demonstrated that the kinetic profile of propofol glucuronidation by liver microsomes markedly differed among humans, monkeys, rats, and mice, and suggest that species and sex differences exist in the roles of UGT isoform(s), including UGT1A9, involved in its metabolism.
authors.forename: M
authors.initials: M
authors.lastname: Mukai
authors.forename: T
authors.initials: T
authors.lastname: Isobe
authors.forename: K
authors.initials: K
authors.lastname: Okada
authors.forename: M
authors.initials: M
authors.lastname: Murata
authors.forename: M
authors.initials: M
authors.lastname: Shigeyama
authors.forename: N
authors.initials: N
authors.lastname: Hanioka
mesh_terms: D000328:Adult; D000368:Aged; D018686:Anesthetics, Intravenous / Q000493:pharmacokinetics*; D000818:Animals; D005260:Female; D020719:Glucuronides / Q000378:metabolism; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism*; D008875:Middle Aged; D015742:Propofol / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D012727:Sex Characteristics; D013045:Species Specificity; D055815:Young Adult
chemical_list: D018686:Anesthetics, Intravenous; D020719:Glucuronides; D015742:Propofol