Deuterium isotope effects in drug pharmacokinetics II: Substrate-dependence of the reaction mechanism influences outcome for cytochrome P450 cleared drugs

PLoS One. 2018 Nov 14;13(11):e0206279. doi: 10.1371/journal.pone.0206279. eCollection 2018.

Abstract

Two chemotypes were examined in vitro with CYPs 3A4 and 2C19 by molecular docking, metabolic profiles, and intrinsic clearance deuterium isotope effects with specifically deuterated form to assess the potential for enhancement of pharmacokinetic parameters. The results show the complexity of deuteration as an approach for pharmacokinetic enhancement when CYP enzymes are involved in metabolic clearance. With CYP3A4 the rate limiting step was chemotype-dependent. With one chemotype no intrinsic clearance deuterium isotope effect was observed with any deuterated form, whereas with the other chemotype the rate limiting step was isotopically sensitive, and the magnitude of the intrinsic clearance isotope effect was dependent on the position(s) and extent of deuteration. Molecular docking and metabolic profiles aided in identifying sites for deuteration and predicted the possibility for metabolic switching. However, the potential for an isotope effect on the intrinsic clearance cannot be predicted and must be established by examining select deuterated versions of the chemotypes. The results show how in a deuteration strategy molecular docking, in-vitro metabolic profiles, and intrinsic clearance assessments with select deuterated versions of new chemical entities can be applied to determine the potential for pharmacokinetic enhancement in a discovery setting. They also help explain the substantial failures reported in the literature of deuterated versions of drugs to elicit a systemic enhancement on pharmacokinetic parameters.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cytochrome P-450 CYP2C19 / chemistry*
  • Cytochrome P-450 CYP2C19 / radiation effects
  • Cytochrome P-450 CYP3A / chemistry*
  • Cytochrome P-450 CYP3A / radiation effects
  • Deuterium / chemistry*
  • Deuterium / pharmacology
  • Heme / chemistry
  • Heme / radiation effects
  • Humans
  • Inactivation, Metabolic
  • Kinetics
  • Microsomes / radiation effects
  • Molecular Docking Simulation
  • Oxidation-Reduction / radiation effects
  • Pharmacokinetics*
  • Substrate Specificity

Substances

  • Heme
  • Deuterium
  • Cytochrome P-450 CYP2C19
  • Cytochrome P-450 CYP3A

Grants and funding

This work was funded by Pfizer. All authors were employed by Pfizer Inc at the time this work was done. Pfizer provided support in the form of salaries for all authors, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.