Pharmacokinetics of novel inhibitors of androgen synthesis after intravenous administration in mice.

Purpose. The pharmacokinetics of several new androgen synthesis inhibitors were investigated after intravenous administration in mice. The inhibitors were: 3β-hydroxy-17-(1H-imidazol-1-yl)androsta-5,16-diene (VN/85-1), 3β-hydroxy-17-(1H-1,2,3-triazol-1-yl)androsta-5,16-diene (VN/87-1), 17-(1H-imidazol-1-yl)androsta-4,16-diene-3-one (VN/108-1) and 17-(5′-isoxazolyl)androsta-4,16-dien-3-one (L-39). Methods. Male Balb/c mice were injected with VN/85-1, VN/87-1, VN/108-1 or L-39 at 10, 25 and 50 mg/kg doses. Blood was collected at various times after drug administration via the eye orbit. The concentrations of VN/85-1, VN/87-1, VN/108-1 or L-39 in plasma were analyzed by a reversed-phase HPLC method with UV detection. Results. The plasma levels of VN/85-1, VN/87-1, VN/108-1 and L-39 declined biexponentially with terminal elimination half-lives ranging from 0.88 to 1.77 h. The terminal half-lives for VN/87-1, VN/85-1 and VN/108-1 were similar. However, the terminal half-life for L-39 was significantly longer than those for VN/87-1, VN/85-1 and VN/108-1. The systemic clearance values for the steroids ranged from 0.85 to 10.91 l/h per kg with a rank order of their clearance of L-39>VN/87-1>VN/108-1>VN/85-1. The apparent volumes of distribution at steady state for the steroids ranged from 0.58 to 18.85 l/kg with a rank order of their apparent V_ss of L-39>VN/87-1>VN/85-1>VN/108-1. The clearance and apparent V_ss for all four compounds were dose-independent following intravenous administration of doses up to 50 mg/kg. Conclusions. VN/85-1, VN/87-1, VN/108-1 and L-39 are rapidly cleared from the systemic circulation and display linear pharmacokinetics in mice. The information presented may be used to improve the disposition profiles and activities of the steroidal inhibitors of androgen synthesis in animal models of prostate cancer. [ABSTRACT FROM AUTHOR]