Dataset Information

An Unexpected Deuterium-Induced Metabolic Switch in Doxophylline.

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.

SUBMITTER: Aprile S

PROVIDER: S-EPMC9377007 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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An Unexpected Deuterium-Induced Metabolic Switch in Doxophylline.

Aprile Silvio S Colombo Giorgia G Serafini Marta M Di Paola Rosanna R Pisati Federica F Bhela Irene Preet IP Cuzzocrea Salvatore S Grosa Giorgio G Pirali Tracey T

ACS medicinal chemistry letters 20220714 8

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 ...[more]

PMID: 35978700

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Project description:BackgroundMagnetic resonance (MR) imaging of deuterated glucose, termed deuterium metabolic imaging (DMI), is emerging as a biomarker of pathway-specific glucose metabolism in tumors. DMI is being studied as a useful marker of treatment response in a scan-rescan scenario. This study aims to evaluate the repeatability of brain DMI.MethodsA repeatability study was performed in healthy volunteers from December 2022 to March 2023. The participants consumed 75 g of [6,6'-2H2]glucose. The delivery of 2H-glucose to the brain and its conversion to 2H-glutamine + glutamate, 2H-lactate, and 2H-water DMI was imaged at baseline and at 30, 70, and 120 min. DMI was performed using MR spectroscopic imaging on a 3-T system equipped with a 1H/2H-tuned head coil. Coefficients of variation (CoV) were computed for estimation of repeatability and between-subject variability. In a set of exploratory analyses, the variability effects of region, processing, and normalization were estimated.ResultsSix male participants were recruited, aged 34 ± 6.5 years (mean ± standard deviation). There was 42 ± 2.7 days between sessions. Whole-brain levels of glutamine + glutamate, lactate, and glucose increased to 3.22 ± 0.4 mM, 1.55 ± 0.3 mM, and 3 ± 0.7 mM, respectively. The best signal-to-noise ratio and repeatability was obtained at the 120-min timepoint. Here, the within-subject whole-brain CoVs were -10% for all metabolites, while the between-subject CoVs were -20%.ConclusionsDMI of glucose and its downstream metabolites is feasible and repeatable on a clinical 3 T system.Trial registrationClinicalTrials.gov, NCT05402566 , registered the 25th of May 2022.Relevance statementBrain deuterium metabolic imaging of healthy volunteers is repeatable and feasible at clinical field strengths, enabling the study of shifts in tumor metabolism associated with treatment response.Key points• Deuterium metabolic imaging is an emerging tumor biomarker with unknown repeatability. • The repeatability of deuterium metabolic imaging is on par with FDG-PET. • The study of deuterium metabolic imaging in clinical populations is feasible.

Dataset Information

An Unexpected Deuterium-Induced Metabolic Switch in Doxophylline.

Publications

An Unexpected Deuterium-Induced Metabolic Switch in Doxophylline.

Similar Datasets

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