Metabolism and <i>in vitro</i> drug–drug interaction assessment of viloxazine
Creators: name: Chungping Yu
Publisher: name: Taylor & Francis
Year: 2020
Subjects: subject: Biochemistry
subject: Medicine
subject: Microbiology
subject: FOS: Biological sciences
subject: FOS: Biological sciences
subject: Cell Biology
subject: Genetics
subject: Molecular Biology
subject: Physiology
subject: Pharmacology
subject: Biotechnology
subject: 39999 Chemical Sciences not elsewhere classified
subject: FOS: Chemical sciences
subject: FOS: Chemical sciences
subject: Cancer
subject: 111714 Mental Health
subject: FOS: Health sciences
subject: FOS: Health sciences

description: Viloxazine is currently being developed as a treatment for attention deficit/hyperactivity disorder (ADHD). The aim of these studies is to update the understanding of the rat and human metabolism and the <i>in vitro</i> drug–drug interaction profile of viloxazine to a degree where it meets current regulatory standards for such investigations.<i>In vivo</i> absorption-distribution-metabolism-excretion (ADME) studies demonstrated that in humans 5-hydroxylation followed by glucuronidation is the major metabolic route. This route was also seen as a minor route in rats where the major route is O-deethylation with subsequent sulfation.In humans, the 5-hydoxylation pathway is mediated by CYP2D6. An estimate for the fraction of the metabolism via this pathway suggests a PM/EM difference of &lt;2-fold, making it highly unlikely that this will be an issue of clinical significance.Viloxazine forms a unique N-carbamoyl glucuronide in humans. The chemical reactivity characteristics of this metabolite are similar to stable glucuronide conjugates and dissimilar from acyl glucuronides; therefore, it is regarded as a stable Phase II conjugate.<i>In vitro</i> drug–drug interaction (DDI) testing indicates that viloxazine is not a significant inhibitor or inducer of CYPs and transporters with the exception of CYP1A2. Viloxazine is currently being developed as a treatment for attention deficit/hyperactivity disorder (ADHD). The aim of these studies is to update the understanding of the rat and human metabolism and the <i>in vitro</i> drug–drug interaction profile of viloxazine to a degree where it meets current regulatory standards for such investigations. <i>In vivo</i> absorption-distribution-metabolism-excretion (ADME) studies demonstrated that in humans 5-hydroxylation followed by glucuronidation is the major metabolic route. This route was also seen as a minor route in rats where the major route is O-deethylation with subsequent sulfation. In humans, the 5-hydoxylation pathway is mediated by CYP2D6. An estimate for the fraction of the metabolism via this pathway suggests a PM/EM difference of &lt;2-fold, making it highly unlikely that this will be an issue of clinical significance. Viloxazine forms a unique N-carbamoyl glucuronide in humans. The chemical reactivity characteristics of this metabolite are similar to stable glucuronide conjugates and dissimilar from acyl glucuronides; therefore, it is regarded as a stable Phase II conjugate. <i>In vitro</i> drug–drug interaction (DDI) testing indicates that viloxazine is not a significant inhibitor or inducer of CYPs and transporters with the exception of CYP1A2.