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

• Published in: PloS one 2018-11, Vol.13 (11), p.e0206279-e0206279
• Main Authors: Sun, Hao, Piotrowski, David W, Orr, Suvi T M, Warmus, Joseph S, Wolford, Angela C, Coffey, Steven B, Futatsugi, Kentaro, Zhang, Yinsheng, Vaz, Alfin D N
• Format: Article
• Language: English
• Subjects: Biology and Life Sciences; Constraining; Cytochrome; Cytochrome P-450 CYP2C19 - chemistry; Cytochrome P-450 CYP2C19 - radiation effects; Cytochrome P-450 CYP3A - chemistry; Cytochrome P-450 CYP3A - radiation effects; Cytochrome P450; Cytochromes P450; Dependence; Deuteration; Deuterium; Deuterium - chemistry; Deuterium - pharmacology; Drugs; Enzymes; Heme - chemistry; Heme - radiation effects; Humans; Hydrogen; Inactivation, Metabolic; Isotope effect; Kinetics; Medicine; Medicine and Health Sciences; Metabolism; Metabolites; Microsomes - radiation effects; Molecular docking; Molecular Docking Simulation; Organic chemistry; Oxidation-Reduction - radiation effects; Parameters; Pharmacokinetics; Pharmacology; Physical Sciences; Proteins; R&D; Reaction mechanisms; Research & development; Substrate Specificity; Substrates
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0206279

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.