Metabolism and enantioselective pharmacokinetics of Casodex in man

1. Five healthy male volunteers received a single oral dose (50 mg; 42 microCi) of 14C-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 48 h after dosing and, thereafter, declined monoexponentially 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 first 2-5 h, and then declined monoexponentially with a mean half-life of 19 h. Plasma concentrations of the racemate were in very good agreement with the sum of the enantiomer concentrations throughout the study and were very similar to concentrations of total radioactivity over the first 4 days. 3. About 80% of the radioactive dose was recovered in urine (35.8 +/- 1.7%; mean +/- SEM) and faeces (42.6 +/- 2.9%) during a total collection over 9 days; this incomplete recovery was consistent with the slow elimination of R-Casodex. 4. T.l.c. of urine extracts indicated extensive metabolism of Casodex to two polar metabolites identified as the glucuronide conjugates of Casodex and hydroxy-Casodex; almost no parent compound was observed. Virtually all of the Casodex glucuronide excreted in urine during the first 2 days was derived from S-Casodex, consistent with the relatively low plasma concentrations and rapid elimination of this enantiomer. 5. T.l.c. of faecal extracts showed the presence of both Casodex and hydroxy-Casodex; these may have been eliminated in bile as the glucuronide conjugates, with subsequent hydrolysis in the intestinal tract.