Pharmacokinetic profile of 3 beta-hydroxy-17-(1H-1,2,3-triazol-1-yl)androsta-5,16-diene (VN/87-1), a potent androgen synthesis inhibitor, in mice

The objective of this study was to assess the pharmacokinetics and bioavail ability of 3 beta -hydroxy-17-(1H-1,2,3-triazol-1-yl)androsta-5,16-diene (V N/87-1) in normal male mice and in SCID mice bearing human LNCaP tumor xeno grafts. VN/87-1 is a novel potent steroidal inhibitor of human testicular 1 7-alpha -hydroxylase/C-17,C-20-lyase. The steroid also shows anti-androgeni c activity and inhibits the growth of human prostate cancer cell lines (LNC aP) in vitro and in vivo. Male Balb/c mice were given single oral, subcutan eous (s.c.) or intravenous (i.v.) bolus dose of VN/87-1 (25, 50 or 100 mg/k g). Male SCID mice bearing LNCaP tumor xenografts were injected with a sing le s.c. dose of VN/87-1 (50 mg/kg). The animals were sacrificed at various times up to 24 h after drug administration and blood was collected. The pla sma samples were prepared and analyzed by a reversed phase HPLC system equi pped with a diode array detector. A non-compartmental pharmacokinetic appro ach was used to evaluate the plasma level versus time data. Following i.v. administration of VN/87-1, the plasma levels declined exponentially with an elimination half-life of 1.2 +/- 0.03 h. The absolute bioavailability of t he 50 mg/kg dose after oral or s.c. administration was 12.08 +/- 2 or 57.2 +/- 4.5%, respectively. VN/87-1 is a high clearance (5.0 +/- 1.3 l/h per kg ) compound in mice and its volume of distribution was relatively large (6.5 +/- 1.2 l/kg). The pharmacokinetic parameters of VN/87-1 were not signific antly altered in SCID mice bearing human LNCaP tumor xenografts. VN/87-1 is well absorbed from the subcutaneous site compared with absorption from the gastrointestinal tract and shows linear kinetics at doses up to 100 mg/kg. (C) 2001 Published by Elsevier Science Ltd.