Abiraterone

Abiraterone is a potent and irreversible CYP17A1 inhibitor with antiandrogen activity, which inhibits both the 17α-hydroxylase and 17,20-lyase activity of the cytochrome p450 enzyme CYP17 with IC₅₀s of 2.5 nM and 15 nM, respectively. IC50 & Target: IC50:17α-hydroxylase (2.5 nM), 17,20-lyase (15 nM)^[6] In Vitro: Significant inhibition of proliferation of the AR-positive prostate cancer cell lines LNCaP and VCaP with doses of Abiraterone ≥5 μM is confirmed^[2]. Abiraterone shows IC₅₀ values of 15 nM and 2.5 nM for the 17,20-lyase and 17α-hydroxylase (CYP17 is a bifunctional enzyme with both 17α-hydroxylase and 17,20-lyase activity). Abiraterone inhibits human 17,20-lyase and 17α-hydroxylase with IC₅₀ of 27 and 30 nM respectively^[3]. Abiraterone inhibits recombinant human 3βHSD1 and 3βHSD2 activity with competitive K_i values of 2.1 and 8.8 μM. 10 μM Abiraterone is sufficient to completely block synthesis of 5α-dione and DHT in both cell lines.Treatment with abi significantly inhibited CRPC progression in the robustly growing subset, effectively putting a ceiling on tumor growth over 4 weeks of treatment (P<0.00001). [³H]-dehydroepiandrosterone (DHEA) depletion and Δ⁴-androstenedione (AD) accumulation are inhibited by Abiraterone in LNCaP, with an IC₅₀<1 μM^[4]. In Vivo: The 0.5 mmol/kg/d Abiraterone treatment dose is previously shown to yield serum concentrations of about 0.5 to 1 μM. Xenograft tumor growth in the control group is widely variable, with some tumors growing slowly and only a subset of tumors exhibiting robust growth^[4]. Following i.v. administration (5 mg/kg) the clearance (Cl) and volume of distribution (V_d) are found to be 31.2 mL/min/kg and 1.97 L/kg, respectively. The AUC_0-∞ (area under the plasma concentration-time curve from time zero to infinity time point) is found to be 2675 ng*h/mL. The terminal half-life (t_1/2) is 0.73 h. Because of high clearance, Abiraterone (ART) is quantifiable only until 2 h following i.v. administration^[5].