Metabolism of 3-Acetamido-6-methyl-8-n-propyl-s-triazolo [4,3-a]pyrazine (I.C.I. 58,301) in Animals

Abstract

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 active than I.C.I. 58,301.

6. Interspecies differences in metabolism appear to be quantitive rather than qualitative.