Metabolism and enantioselective pharmacokinetics of Casodex in man

Abstract

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.

Pharmacokinetics and Pharmacodynamics of Nonsteroidal Androgen Receptor Ligands

“…As a structural analog, bicalutamide shares the amide bond structure with flutamide. However, amide bond hydrolysis was observed in rat, but not in humans (30,31) (Fig. 4B), which could explain the prolonged half life of bicalutamide in humans.…”

Pharmacokinetics and Metabolism of a Selective Androgen Receptor Modulator in Rats: Implication of Molecular Properties and Intensive Metabolic Profile to Investigate Ideal Pharmacokinetic Characteristics of a Propanamide in Preclinical Study

“…Knowing the interspecies differences in metabolism of bicalutamide, flutamide, and nilutamide (Neri, 1989;Creaven et al, 1991;Boyle et al, 1993;McKillop et al, 1993), additional in vitro and in vivo studies of S-1 should be considered to evaluate the potential toxicity of S-1 and its metabolites in different species. Although in vitro and preclinical measurements cannot be interpreted directly into prediction of drug-induced toxicity, either in animals or in humans (Baillie et al, 2002), choices can be made in selection of lead compounds in preclinical or clinical development.…”

Characterization of the in Vitro Metabolism of Selective Androgen Receptor Modulator Using Human, Rat, and Dog Liver Enzyme Preparations

“…Recombinant human P450 enzyme and insect cell control (Supersomes), pooled human, rat, and dog liver microsome, cytosol, and S9 preparations were purchased from BD Gentest (Woburn, MA). 4Ј-Hydroxy- (Katchen and Buxbaum, 1975) and bicalutamide (B) McKillop et al, 1993).…”

“…The metabolic profiles of flutamide and bicalutamide have been well characterized (Katchen and Buxbaum, 1975;Boyle et al, 1993;McKillop et al, 1993). Hydrolysis of the amide bond and oxidation of the aromatic rings are the major phase I metabolism pathways for both flutamide and bicalutamide (Fig.…”