EXCRETION AND METABOLISM OF TIPREDANE, A NOVEL GLUCOCORTICOID, IN THERAT, MOUSE, MONKEY, AND HUMAN

The excretion and metabolism of [H-3]tipredane, a novel glucocorticoid , has been studied in mice, rats, marmosets, rhesus and cynomolgus mon keys, and humans. After oral administration, [H-3]tipredane was rapidl y absorbed, metabolized, and excreted into urine and feces. In mice an d male rats, radioactivity was excreted primarily into feces or bile, whereas in female rats, monkeys, and humans, excretion was mainly via the renal route. Some sex differences in the proportions excreted into urine and feces were noted in rodents, with females eliminating relat ively more radioactivity in urine. Tipredane was shown to be extensive ly metabolized, but the routes were highly species-dependent and, in t he rat, they were sex-dependent. Unchanged tipredane was not detected in any urine, bile, or blood extracts. Urinary and blood extract profi les indicated that there were between 10 and 30 metabolites in rats an d mice, the majority of which constituted <2% of the dose. In these sp ecies, the major pathways involved loss of the thioethyl moiety, S-oxi dation of the thiomethyl group, and saturation of the adjacent saturat ed C16-17 bond. Hydroxylation of the steroid B-ring was seen in the 7 alpha-position in mice and female rats, and in the 6 beta-position in male rats. Metabolism of tipredane in rhesus and cynomolgus monkeys an d humans was similar, but less extensive and different to that seen in rodents. The major products, the 6 beta-hydroxylated sulfoxide and su lfone metabolites of tipredane, accounted for 21-36% of the dose in hu man and monkey urine, and were also major components in blood, In cont rast to mice and rats, S-oxidation and an unsaturated C16-17 bond were evident in primates. Metabolism of tipredane was rapid and complex, w ith significant species differences, although the disposition in rhesu s and cynomolgus monkeys seemed to be similar to humans.