Deuterium Isotope Effects on Drug Pharmacokinetics. I. System- Dependent Effects of Specific Deuteration with Aldehyde Oxidase Cleared Drugs

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 drugs 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 impact the in vivo outcome. Overall, in order 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; 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.