An Unexpected Deuterium-Induced Metabolic Switch in Doxophylline
Silvio Aprile, Giorgia Colombo, M. Teresa Serafini, Rosanna Di Paola, Federica Pisati, Irene Preet Bhela, Salvatore Cuzzocrea, Giorgio Grosa, Tracey Pirali
Abstract
Precision deuteration has become part of the medicinal chemist's toolbox, but its usefulness can be undermined by unpredictable metabolic switch effects. Herein we report the deuteration of doxophylline, a drug used in the treatment of asthma and COPD that undergoes extensive oxidative metabolism. Labeling of the main metabolic soft spots triggered an unexpected multidirectional metabolic switch that, while not improving the pharmacokinetic parameters, changed the metabolic scenario and, in turn, the pharmacodynamic features in two murine models of lung injury.
Topics & Concepts
PharmacodynamicsMetabolic networkMetabolic pathwayDrug discoveryComputational biologyDrugChemistryToolboxMetabolismPharmacologyMedicinePharmacokineticsComputer scienceBiologyBiochemistryProgramming languageChemical Reactions and IsotopesMass Spectrometry Techniques and ApplicationsPharmacogenetics and Drug Metabolism