Tissue distribution and metabolism in rat of an ethynesulphonamide with filaricidal activity

Abstract

1. The tissue distribution and metabolism of a new filaricidal agent P903 (N -\[(2- phenylethynyl)sulfonyl]morpholine) were studied in rat. 2. After s.c. administration of C and C P903, the Tmax in the bloodwas observed on day 2. Elimination was slow and 95% was bound to protein. Radioactivity was distributed in the whole organism but particularly in erythrocytes and the lymphatic channel. Four days later, 60% of the radioactivity was excreted in urine and faeces at equal amounts and 15% remained at the injection point. 3. In all biological fluids tested no P903 was found but only its metabolites. 4. One principal metabolite, the N -\[(2-phenyloxo-2-ethane) sulphonyl] morpholine or oxosulphonamide was identified in blood, urine and faeces as compared with the reference compound by GC MS and NMR. This latter molecule was detected following hydrolysis by hydrochloric acid but not with beta glucuronidase sulphatase. 5. Unconjugated and conjugated oxosulphonamide represented 85% of the radio activity at all times tested in blood but only 38 and 35% respectively of urinary and faecal radioactivity on day 1 after the administration of the labelled drug. 6. Thus, P903 is rapidly converted toareactive metabolite, probably anoxirene, which is then conjugated with endogenous components toform conjugated oxosulphonamide and anunknown metabolite. The role ofthis reactive metabolite in antifilarialactivity seems to be very important in understanding the mechanism of action of P903.