Metabolism and in vitro drug-drug interaction assessment of viloxazine.
Xenobiotica, 2020/11;50(11):1285-1300.
Yu C[1]
Affiliations
PMID: 32394778DOI: 10.1080/00498254.2020.1767319
Impact factor: 1.997
Abstract
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 in vitro drug-drug interaction profile of viloxazine to a degree where it meets current regulatory standards for such investigations. In vivo 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 <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. In vitro drug-drug interaction (DDI) testing indicates that viloxazine is not a significant inhibitor or inducer of CYPs and transporters with the exception of CYP1A2.
Keywords: ADHD; Viloxazine; absorption-distribution-metabolism-excretion (ADME); cytochrome P450; drug–drug interaction
MeSH terms
Antidepressive Agents, Second-Generation; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP2D6; Cytochrome P-450 Enzyme System; Drug Interactions; Glucuronides; Humans; Microsomes, Liver; Viloxazine
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