METABOLISM AND ENANTIOSELECTIVE PHARMACOKINETICS OF CASODEX IN MAN

1. Five healthy male volunteers received a single oral dose (50 mg; 42 muCi) of C-14-Casodex, a racemic compound, which has its antiandrogen activity predominantly in R-Casodex, the (-)-enantiomer, with little activity in S-Casodex, the (+)-enantiomer. 2. Plasma concentrations of R-Casodex increased slowly in all subjects to reach a peak of 559-970 ng/ml between 15 and 48h after dosing and, thereafter, declined mono- exponentially with a mean half-life of 4.2 days. Plasma concentrations of S-Casodex rose rapidly to reach a peak of 32-66 ng/ml within the f irst 2-5 h, and then declined monoexponentially with a mean half-life of 19 h. Plasma concentrations of the racemate were in very good agree ment with the sum of the enantiomer concentrations throughout the stud y and were very similar to concentrations of total radioactivity over the first 4 days. 3. About 80% of the radioactive dose was recovered i n urine (35.8+/-1.7%; mean +/-SEM) and faeces (42.6+/-2.9%) during a t otal collection over 9 days; this incomplete recovery was consistent w ith the slow elimination of R-Casodex. 4. T.l.c. of urine extracts ind icated extensive metabolism of Casodex to two polar metabolites identi fied as the glucuronide conjugates of Casodex and hydroxy-Casodex; alm ost no parent compound was observed. Virtually all of the Casodex gluc uronide excreted in urine during the first 2 days was derived from S-C asodex, consistent with the relatively low plasma concentrations and r apid elimination of this enantiomer. 5. T.l.c. of faecal extracts show ed the presence of both Casodex and hydroxy-Casodex; these may have be en eliminated in bile as the glucuronide conjugates, with subsequent h ydrolysis in the intestinal tract.