Influence of metabolism on the activity of a new anti-fertility agent, 2-(3-ethoxyphenyl)-5,6-dihydro-s-triazolo [5,1-a]isoquinoline (DL 204-IT), in the rat and the hamster.

The activity of a new non-hormonal anti-fertility agent, 2-(3-ethoxyphenyl)-5,6-dihydro-s-triazolo[5,1-a]isoquinoline (DL 204-IT), effective in terminating pregnancy after i.m. or s.c. treatment, was tested after single and multiple oral doses given to rats and hamsters. Although the compound was absorbed well from the gastrointestinal tract and the plasma levels of the radioactivity administered were rather high and sustained, the oral activity was by two orders of magnitude lower than the parenteral one. The plasma profile of the metabolites found after both p.o. and i.m. administration indicates that the compound is rapidly metabolized. Seven metabolites (I-VII) were isolated from the urine of pregnant rats and fully characterized by MS, IR and NMR spectroscopy. They are 2-(3-hydroxyphenyl)-5,6-dihydro-s-triazolo[5,1-a]isoquinoline (I); 2-(3,4-dihydroxyphenyl)-5,6-dihydro-s-triazolo[5,1-1]isoquinoline (II); 2-(3-hydroxyphenyl)-5,6-dihydro-6 beta-hydroxy-s-triazolo[5,1-a]isoquinoline (III); metabolite I-sulphate ester (IV); metabolite III-3-sulphate ester (V); metabolite I-beta-D-glucuronide (VI) and metabolite II-3-beta-D-glucuronide (VII). Metabolite I was shown to be from 1/10 (rat) to 1/30 (hamster) as active as the parent compound, while metabolites II and III were completely inactive. The very low oral activity of DL 204-IT seems to be due mainly to its rapid biotransformation.