Pharmacokinetics and metabolism of formestane in breast cancer patients

Formestane (Lentaron (R), 4-hydroxyandrostznedione) is a steroidal aromatas e inhibitor used for treatment of advanced breast cancer. Clinically, it is administered as a depot form once fortnightly by intramuscular (i.m.) inje ction. To investigate the pharmacokinetics. bioavailability and metabolism of the drug, seven patients received single 250 mg i.m. doses of commercial formestane on Days 0, 21, 35, 49 and 63 of this trial. On Day 63, three of the patients received an additional single intravenous (i.v.) pulse dose o f 1 mg of C-14-labelled formestane. The plasma kinetics after i.m. dosing c onfirmed a sustained release of formestane from the site of injection. With in 24-48 h of the first dose. the circulating drug reached a C-max of 48.0 +/- 20.9 nmol/l (mean +/- S.D.; N = 7). At the end of the dosing interval, after 14 days, the plasma concentration was still at 2.3 +/- 1.8 nmol/l. Th e kinetic variables did not significantly change during prolonged treatment . Intramuscular doses appear to be fully bioavailable. Following i.v. injec tion of C-14-formestane, the unchanged drug disappeared rapidly from plasma . the terminal elimination half-lift being 18 +/- 7 min (N = 3. Plasma clea rance, CL was 4.2 +/- 1.3 1/(h kg) and the terminal distribution volume V-2 was 1.8 +/- 0.51/kg. The drug is mainly eliminated by metabolism. renal ex cretion of metabolites accounting for 95% of dose. The excretory balance of C-14-compounds in urine and faeces totals up to 98.9 +/- 0.8% of the i.v, dose after 168 h. The C-14-compounds in plasma and urine were separated by HPLC, and three major metabolites were submitted to structural analysis by MS, NMR and UV spectroscopy. One of the metabolites is the direct 4-O-glucu ronide of formestane. The other two represent 3-O-sulfates of the exocons 3 beta ,4 beta -dihydroxy-5 alpha -androstane-17-one and 3 beta ,4 beta -dih ydroxy-5 alpha -androstane-17-one, their ratio being 7:3. These exocons are formed by stereoselective 3-keto reduction. accompanied by reduction of th e 4.5-enol function. The exocons do not inhibit human placental aromatase a ctivity in vitro. (C) 2001 Elsevier Science Ltd. All rights reserved.