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.
Highlights
Because of the potential to enhance pharmacokinetic properties or decrease toxicity by virtue of a kinetic deuterium isotope effect, the replacement of hydrogen by deuterium at nonexchangeable carbon-hydrogen bonds of drug molecules has received extensive attention as indicated by an exponential increase over the past decade in patent applications for deuterated versions of existing pharmaceuticals and new chemical entities [1,2]
Using virtual molecular docking with CYPs 3A4 and 2C19, metabolic profiles and intrinsic clearance isotope effects with human liver microsomes and recombinant CYPs 3A4 and 2C19 with deuterated versions of 1a and 2a, we demonstrate the mechanistic complexities of CYP-catalyzed reactions where the rate limiting step may be determined by the substrate under consideration
While substitution of deuterium for hydrogen without impactful changes in physico-chemical properties of drug molecules is an attractive proposition for improving the pharmacokinetic or toxicological properties of drugs, differences in reaction mechanisms of the enzymes involved in their metabolic clearance can impact the outcome
Summary
Because of the potential to enhance pharmacokinetic properties or decrease toxicity by virtue of a kinetic deuterium isotope effect, the replacement of hydrogen by deuterium at nonexchangeable carbon-hydrogen bonds of drug molecules has received extensive attention as indicated by an exponential increase over the past decade in patent applications for deuterated versions of existing pharmaceuticals and new chemical entities [1,2]. KDIE CYP 3A4 these authors are articulated in the ‘author contributions’ section
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