title: Pharmacokinetics and absolute bioavailability of epristeride in healthy male subjects.
abstract: The objective of the current investigation was to describe the pharmacokinetics and absolute oral bioavailability of epristeride. Twelve healthy male subjects (mean (SD) age, 27 (6.2) years) received a single oral dose of 5 mg and an intravenous infusion of 4.5 mg over 30 min in a crossover fashion. Blood samples were obtained over 72h for the determination of epristeride plasma concentrations using a sensitive high-performance liquid chromatography assay. The lower limit of quantification was 5 ng mL-1. Pharmacokinetic analysis of the plasma concentration-time data was performed by both non-compartmental and compartmental methods. Absolute bioavailability was determined using dose-normalized AUC values following oral and intravenous administration. Epristeride plasma concentrations declined in a biexponential fashion with secondary peaks evident around 24 h in a majority of subjects following both routes of administration. Maximal plasma concentrations were typically achieved approximately 4 h after oral dosing. The mean apparent terminal elimination half-life estimates were similar following intravenous and oral administration and were 27.3 and 26.2 h, respectively. The mean plasma clearance and steady-state volume of distribution were 0.33 (0.09) mL min-1 kg-1 and 0.54 (0.17) L kg-1, respectively. The mean absolute bioavailability was 93% (95% CI: 84%, 104%). Following compartmental analysis of the intravenous data, the mean (SD) lambda 1 and lambda 2 half-life estimates were 2.74 (0.48) and 31.8 (19.5) h, respectively. The % AUC associated with the lambda 2 exponential phase was approximately 68%. This long half-life allows for once-daily dosing of epristeride.
authors.affiliation: SmithKline Beecham Pharmaceuticals, King of Prussia, PA, USA.
authors.forename: L J
authors.initials: LJ
authors.lastname: Benincosa
authors.forename: P R
authors.initials: PR
authors.lastname: Audet
authors.forename: D
authors.initials: D
authors.lastname: Lundberg
authors.forename: N
authors.initials: N
authors.lastname: Zariffa
authors.forename: D K
authors.initials: DK
authors.lastname: Jorkasky
mesh_terms: D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000008:administration & dosage; D058891:5-alpha Reductase Inhibitors; D000284:Administration, Oral; D000328:Adult; D000730:Androstadienes / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001682:Biological Availability; D018592:Cross-Over Studies; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male
chemical_list: D058891:5-alpha Reductase Inhibitors; D000730:Androstadienes; C072547:epristeride; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase