Pharmacokinetics and Drug Metabolism Department, Ipsen Pharma, Barcelona, Spain.
Drug Metab Dispos. 2012 Jul;40(7):1268-78. doi: 10.1124/dmd.111.044271. Epub 2012 Mar 26.
Irosustat is a first-generation, irreversible, steroid sulfatase inhibitor currently in development for hormone-dependent cancer therapy. To predict clinical drug-drug interactions between irosustat and possible concomitantly administered medications, the inhibition/induction potential of irosustat with the main drug-metabolizing enzymes was investigated in vitro. The interaction of aromatase inhibitors in the in vitro metabolism of irosustat was also studied. Irosustat inhibited CYP1A2 activity in human liver microsomes through the formation of its desulfamoylated degradation product and metabolite 667-coumarin. CYP1A2 inhibition by 667-coumarin was competitive, with a K(i) of 0.77 μM, a concentration exceeding by only 5-fold the maximal steady-state concentration of 667-coumarin in human plasma with the recommended dose of irosustat. In addition, 667-coumarin metabolites enhanced the inhibition of CYP1A2 activity. Additional clinical interaction studies of irosustat with CYP1A2 substrate drugs are strongly recommended. 667-Coumarin also appeared to be a competitive inhibitor of CYP2C19 (K(i) = 5.8 μM) in human liver microsomes, and this inhibition increased with assessment in human hepatocytes. Inhibition of CYP2C19 enzyme activity was not caused by repression of CYP2C19 gene expression. Therefore, additional mechanistic experiments or follow-up studies with clinical evaluation are recommended. Irosustat neither inhibited CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6, CYP2E1, CYP3A4/5, or UDP-glucuronosyltransferase 1A1, 1A4, or 2B7 activities nor induced CYP1A2, CYP2C9, CYP2C19, or CYP3A4/5 at clinically relevant concentrations. Results from human liver microsomes indicated that no changes in irosustat pharmacokinetics in vivo are expected as a result of inhibition of irosustat metabolism in cases of concomitant medication administration or irosustat-aromatase inhibitor combination therapy with letrozole, anastrozole, or exemestane.
依罗司他是一种第一代、不可逆的甾体硫酸酯酶抑制剂，目前正在开发用于激素依赖性癌症治疗。为了预测依罗司他与可能同时给予的药物之间的临床药物相互作用，本研究在体外研究了依罗司他对主要药物代谢酶的抑制/诱导潜力。还研究了芳香酶抑制剂对依罗司他体外代谢的影响。依罗司他通过形成脱磺酰胺降解产物和代谢物 667-香豆素抑制人肝微粒体中的 CYP1A2 活性。667-香豆素对 CYP1A2 的抑制作用呈竞争性，K(i)为 0.77 μM，浓度仅比依罗司他推荐剂量下 667-香豆素在人血浆中的最大稳态浓度高 5 倍。此外，667-香豆素代谢物增强了对 CYP1A2 活性的抑制作用。强烈建议对依罗司他与 CYP1A2 底物药物的额外临床相互作用研究。667-香豆素似乎也是人肝微粒体中 CYP2C19 的竞争性抑制剂（K(i) = 5.8 μM），并且这种抑制作用随着在人肝细胞中的评估而增加。CYP2C19 酶活性的抑制不是由 CYP2C19 基因表达的抑制引起的。因此，建议进行额外的机制实验或临床评估的随访研究。依罗司他既不抑制 CYP2A6、CYP2B6、CYP2C8、CYP2C9、CYP2D6、CYP2E1、CYP3A4/5 或 UDP-葡萄糖醛酸基转移酶 1A1、1A4 或 2B7 的活性，也不以临床相关浓度诱导 CYP1A2、CYP2C9、CYP2C19 或 CYP3A4/5。人肝微粒体的结果表明，在同时给予药物或依罗司他与来曲唑、阿那曲唑或依西美坦联合治疗的情况下，不会因依罗司他代谢的抑制而导致依罗司他体内药代动力学的变化。
