BIOTRANSFORMATION OF THE ANTIDEPRESSANT-D,L-ROLIPRAM .2. METABOLITE PATTERNS IN MAN, RAT, RABBIT, RHESUS AND CYNOMOLGUS MONKEY

1. The metabolism of D,L-rolipram in man was studied by comparison of h.p.l.c. radiochromatograms of plasma and urine obtained at various ti mes following oral and/or s.c. administration to man, rat, rabbit, and rhesus and cynomolgus monkey. 2. Seven metabolites isolated previousl y from man, rat, and rhesus monkey urine by preparative h.p.l.c. and i dentified by mass spectrometry and n.m.r. analysis were used for metab olite identification. 3. In plasma, 3-5 metabolites were found in addi tion to the unchanged drug. In urine, which was the main excretion rou te for rolipram metabolites, > 10 metabolites were detected but not th e parent compound. 4. Between 40 and 70% of the compounds eliminated r enally, were identified by reference to isolated metabolites. 5. Biotr ansformation proceeded by ether cleavage at the methoxy and pentyloxy groups, and by hydroxylation in positions 2 or 3 of the pentyloxy ring followed by sulphation. 6. In man, not in the other species studied, the 5-position of the pyrrolidone ring was also hydroxylated. This com pound cross-reacted with the antibody raised against rolipram which wa s used formerly for the determination of rolipram in biological fluids .