1. 2-(2 - Ethoxyphenoxymethyl) - 2,3,5,6 -tetrahydro - 1,4 - oxazine (I.C. I. 58,834)* in three 14C-labelled forms, given orally to two male volunteers, was completely absorbed, extensively metabolized and rapidly eliminated via the kidney.2. O-Dealkylation, the major metabolic pathway in the rat, was not significant in man.3. The major component in blood at all times was I.C.I. 58,834, which had a blood half-life of 4 h. The level of 14C in blood at 31 h was near the limit of detection.4. The observed activity of the drug appears to be due to the parent compound alone.

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 animal 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.

1. 3-Acetamido-6-methyl-8-n-propyl-s-[3-14C]triazolo [4,3-a]pyrazine ([14C] I.C.I. 58,301) an antibronchoconstrictor has been prepared and its distribution and metabolism studied in six animal species.2. The compound was well absorbed after oral administration, extensively metabolized, widely distributed in the body and rapidly excreted in urine. In small animals >0.5% of the administered radioactivity could be detected in exhaled air.3. Maximum tissue levels in the guinea pig occurred 1 1/2-2h after an oral dose. Labelled material could be detected in the lung and serum of the guinea pig 5 min after an oral dose (5 mg/kg).4. Six metabolites were identified and together with I.C.I. 58,301 these constituted 90% of the 14C-labelled material in the urine from a rhesus monkey. The principal metabolic pathways involved N-deacetylation and hydroxylation of the alkyl side chains; N-methylation in the heterocyclic ring was also observed.5. Two of the major metabolites have been shown to be biologically less activ...