The disposition and metabolism of I.C.I. 58,834 (viloxazine) in animals

Abstract

1. 2-(2-Ethoxyphenoxymethyl-2,3,5,6-tetrahydro-1,4-oxazine (I.C.I. 58,834) has been prepared in three different 14C-labelled forms and its absorption, distribution, metabolism and elimination studied in six animals species. 2. In all species I.C.I. 58,834 was well absorbed after oral administration and extensively metabolized. Excretion via the kidney was the main route of elimination. 3. In the rat the major metabolic pathway is o-dealkylation and sulphate conjugation; the dealkylated metabolite was detected in brain extracts. A novel type of polar metabolite was isolated from rat urine, apparently a conjugate with sulphate and hippurate. 4. The metabolic pathways in beagle dogs include hydroxylation of the phenyl ring (and subsequent conjugation), N-methylation, formation of the N-methyl-N-oxide, and oxidation of the oxazine ring. 5. Maximum blood levels of I.C.I. 58,834 in dogs were unchanged during eight weeks daily administration and the half-life was 2.5-3 h. I.C.I. 58,834 is the main component in dog blood. Rat serum contains mainly conjugates of dealkylated I.C.I. 58,834 and the parent compound is a minor component. 6. None of the metabolites has significant CNS activity and activity observed following administration of I.C.I. 58,834 is due primarily to the parent compound.