title: Deuterium isotope effects on drug pharmacokinetics. I. System-dependent effects of specific deuteration with aldehyde oxidase cleared drugs.
abstract: The pharmacokinetic properties of drugs may be altered by kinetic deuterium isotope effects. With specifically deuterated model substrates and drugs metabolized by aldehyde oxidase, we demonstrate how knowledge of the enzyme's reaction mechanism, species differences in the role played by other enzymes in a drug's metabolic clearance, and differences in systemic clearance mechanisms are critically important for the pharmacokinetic application of deuterium isotope effects. Ex vivo methods to project the in vivo outcome using deuterated carbazeran and zoniporide with hepatic systems demonstrate the importance of establishing the extent to which other metabolic enzymes contribute to the metabolic clearance mechanism. Differences in pharmacokinetic outcomes in guinea pig and rat, with the same metabolic clearance mechanism, show how species differences in the systemic clearance mechanism can affect the in vivo outcome. Overall, to gain from the application of deuteration as a strategy to alter drug pharmacokinetics, these studies demonstrate the importance of understanding the systemic clearance mechanism and knowing the identity of the metabolic enzymes involved, the extent to which they contribute to metabolic clearance, and the extent to which metabolism contributes to the systemic clearance.
authors.affiliation: Department of Pharmacokinetics Dynamics and Metabolism, Pfizer Global Research and Development, Groton, Connecticut 06340, USA.
authors.forename: Raman
authors.initials: R
authors.lastname: Sharma
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Strelevitz
authors.forename: Hongying
authors.initials: H
authors.lastname: Gao
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Clark
authors.forename: Klaas
authors.initials: K
authors.lastname: Schildknegt
authors.forename: R Scott
authors.initials: RS
authors.lastname: Obach
authors.forename: Sharon L
authors.initials: SL
authors.lastname: Ripp
authors.forename: Douglas K
authors.initials: DK
authors.lastname: Spracklin
authors.forename: Larry M
authors.initials: LM
authors.lastname: Tremaine
authors.forename: Alfin D N
authors.initials: AD
authors.lastname: Vaz
mesh_terms: D042931:Aldehyde Oxidase / Q000378:metabolism*; D000818:Animals; D002219:Carbamates / Q000378:metabolism / Q000493:pharmacokinetics*; D003600:Cytosol / Q000378:metabolism; D003903:Deuterium / Q000378:metabolism*; D006146:Guanidines / Q000378:metabolism / Q000493:pharmacokinetics*; D006168:Guinea Pigs; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008297:Male; D011720:Pyrazoles / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002219:Carbamates; D006146:Guanidines; D011720:Pyrazoles; C031720:carbazeran; C424422:zoniporide; D003903:Deuterium; D042931:Aldehyde Oxidase