Glucuronidation of SN-38, the Active Metabolite of Irinotecan, by Human Hepatic Microsomes

摘要: : We have investigated the glucuronidation in vitro of SN-38, active metabolite irinotecan, a semi-synthetic anticancer drug derived from 20(S)camptothecin. Preparations human hepatic microsomes (final concentration: 1 mg prot./ml), were incubated for hr 0.1 M Tris buffer, pH 7.4, containing 10 mM MgCl2, presence UDP-glucuronic acid (4 mM), saccharolactone and detergent. Microsomes five livers studied individually or as pooled preparation. either its lactone carboxylate form, was added at range concentrations. The SN-38 β-glucuronide formed measured by HPLC with fluorometric detection. reaction appeared linear over these conditions Brij 35 0.5 mg/mg prot. best activator. apparent parameters independent molecular form substrate. half-saturation constant 17-20 μM Vmax 60-75 pmol/min./mg interindividual variation relatively low (ratio 1.8 between extreme values). In addition, effect twelve drugs currently associated irinotecan clinics evaluated this system (drug 100 μM; 5 μM). These produced little if any interference glucuronidation. Therefore, major interferences transformation comedications are unlikely to occur vivo.