Department of Medicine, Indiana University School of Medicine, Indianapolis, USA.
Br J Clin Pharmacol. 2010 Dec;70(6):854-69. doi: 10.1111/j.1365-2125.2010.03791.x.
Little information is available regarding the metabolic routes of anastrozole and the specific enzymes involved. We characterized anastrozole oxidative and conjugation metabolism in vitro and in vivo.
A sensitive LC-MS/MS method was developed to measure anastrozole and its metabolites in vitro and in vivo. Anastrozole metabolism was characterized using human liver microsomes (HLMs), expressed cytochrome P450s (CYPs) and UDP-glucuronosyltransferases (UGTs).
Hydroxyanastrozole and anastrozole glucuronide were identified as the main oxidative and conjugated metabolites of anastrozole in vitro, respectively. Formation of hydroxyanastrozole from anastrozole was markedly inhibited by CYP3A selective chemical inhibitors (by >90%) and significantly correlated with CYP3A activity in a panel of HLMs (r= 0.96, P= 0.0005) and mainly catalyzed by expressed CYP3A4 and CYP3A5. The K(m) values obtained from HLMs were also close to those from CYP3A4 and CYP3A5. Formation of anastrozole glucuronide in a bank of HLMs was correlated strongly with imipramine N-glucuronide, a marker of UGT1A4 (r= 0.72, P < 0.0001), while expressed UGT1A4 catalyzed its formation at the highest rate. Hydroxyanastrozole (mainly as a glucuronide) and anastrozole were quantified in plasma of breast cancer patients taking anastrozole (1 mg day⁻¹); anastrozole glucuronide was less apparent.
Anastrozole is oxidized to hydroxyanastrozole mainly by CYP3A4 (and to some extent by CYP3A5 and CYP2C8). Once formed, this metabolite undergoes glucuronidation. Variable activity of CYP3A4 (and probably UGT1A4), possibly due to genetic polymorphisms and drug interactions, may alter anastrozole disposition and its effects in vivo.
关于阿那曲唑的代谢途径和涉及的特定酶，相关信息较少。我们对阿那曲唑的体外和体内氧化和结合代谢进行了特征描述。
开发了一种灵敏的 LC-MS/MS 方法，用于测量阿那曲唑及其在体外和体内的代谢产物。使用人肝微粒体（HLMs）、表达细胞色素 P450（CYP）和 UDP-葡萄糖醛酸基转移酶（UGTs）对阿那曲唑的代谢进行了特征描述。
在体外，分别鉴定出羟阿那曲唑和阿那曲唑葡萄糖醛酸苷为阿那曲唑的主要氧化和结合代谢产物。CYP3A 选择性化学抑制剂（>90%）显著抑制阿那曲唑生成羟阿那曲唑，并且与 HLMs 中的 CYP3A 活性显著相关（r=0.96，P=0.0005），主要由表达的 CYP3A4 和 CYP3A5 催化。从 HLMs 获得的 K(m) 值也接近 CYP3A4 和 CYP3A5 的 K(m) 值。在一组 HLMs 中，阿那曲唑葡萄糖醛酸苷的形成与作为 UGT1A4 标志物的丙咪嗪 N-葡萄糖醛酸苷强烈相关（r=0.72，P<0.0001），而表达的 UGT1A4 以最高的速率催化其形成。在服用阿那曲唑（1mg 每日）的乳腺癌患者的血浆中定量检测到羟阿那曲唑（主要为葡萄糖醛酸苷）和阿那曲唑；阿那曲唑葡萄糖醛酸苷则不太明显。
阿那曲唑主要被 CYP3A4（在一定程度上也被 CYP3A5 和 CYP2C8）氧化为羟阿那曲唑。一旦形成，这种代谢物会发生葡萄糖醛酸化。CYP3A4（可能还有 UGT1A4）的活性可能因遗传多态性和药物相互作用而发生变化，这可能会改变阿那曲唑在体内的处置及其作用。
