Enantioselective metabolism and pharmacokinetics of Casodex in the male rat

Abstract

1. Casodex, a non-steroidal antiandrogen, is a racemic mixture of R-casodex, the pharmacologically active (-)-enantiomer, and S-Casodex, the inactive (+)-enantiomer. Single oral doses of pseudo-racemic ¹⁴C-Casodex (10 mg/kg), prepared from mixtures of either ¹⁴C-labelled R-Casodex and unlabelled S-Casodex, or ¹⁴C-S-Casodex and unlabelled R-Casodex, were administered to the intact and bile duct-cannulated male rat.

2. Neither enantiomer underwent stereochemical inversion, but the pharmacokinetics of Casodex showed marked enantioselectivity.

3. After dosing R-labelled Casodex, plasma concentrations of R-Casodex increased slowly to reach a peak of 3.50 ± 0.05 μg/ml (mean ± SEM) at 12 h and, thereafter, declined monoexponentially with an elimination half-life of 24 h. Plasma concentrations of S-Casodex rose rapidly to reach a much lower peak of 0.97 ± 0.06 μg/ml at 3 h and, thereafter, declined rapidly, although there were insufficient data to determine the half-life. R-Casodex had a much higher AUC_0–24 (66 μg.h/ml) than S-Casodex (12 μg.h/ml). Plasma drug concentrations measured using an achiral assay were in very good agreement with the sum of the enantiomer concentrations throughout the profile. R-Casodex comprised 94% of the total plasma radioactivity at 12 h, decreasing to 75% at 120 h.

4. Plasma concentration data generated after administration of S-Casodex were similar to those observed after dosing R-labelled Casodex. S-Casodex comprised about 74% of the total plasma radioactivity at 6 h and only 41% at 24 h.

5. The urine of intact animals contained 36 ± 2 and 48 ± 3% of the dose respectively up to 48 and 120 h after dosing with R-labelled Casodex, and 33 ± 4 and 34 ± 4% respectively after dosing with S-labelled Casodex. The urine and bile of the cannulated rat contained 43 ± 2 and 21 ± 2% of the dose respectively up to 48 h after dosing with R-labelled Casodex and 37 (n = 2) and 50% respectively after dosing with S-labelled Casodex.

6. After dosing with R- or S-labelled Casodex, the urinary radioactivity consisted of the carboxylic acid metabolite formed by hydrolytic cleavage at the amide, whereas biliary radioactivity consisted of hydroxy-Casodex and Casodex, mainly conjugated with glucuronic acid. The clearance of R-Casodex by each of these pathways of metabolism was less than that of S-Casodex, with direct glucuronidation and hydroxylation showing greater enantioselectivity than hydrolysis.