Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, San Diego, CA 92121, USA.
Curr Drug Metab. 2010 May;11(4):296-306. doi: 10.2174/138920010791514207.
PF-02341066 is a selective c-Met/Alk tyrosine kinase inhibitor currently in clinical development as an anticancer agent. Non-clinical toxicokinetic evaluation in rats revealed gender-related differences in pharmacokinetics with at least 2-fold higher PF-02341066 plasma concentrations in males than females when administered the same dose. In general, lower systemic exposure of drugs that undergoes oxidative metabolism in male than female rats has been well known to be attributed to gender-specific expression of CYP genes in rats. It is of interest to understand why the gender-related pharmacokinetics in rats for PF-02341066 was opposite to the general observations and if the gender-related pharmacokinetics would be seen in humans that may impact the drug efficacy and toxicity profiles. The potential gender-related differences in PF-02341066 metabolism were investigated both in vitro and in vivo using [(3)H]PF-02341066. Oxidation was found to be the major metabolic pathway in male rat liver S9 incubations whereas sulfoconjugation was the predominant metabolic pathway in females. There was no qualitative difference in metabolite profiles of PF-02341066 between man and woman liver S9 incubations. Following a single oral administration of [(3)H]PF-02341066 to rats at 150 mg/kg, the primary route of excretion of the radioactivity was via feces, in which, the most abundant radio-component in male rat was the parent drug (29% of dose) and in female rat was the parent sulfate (44% of dose). The more extensive formation of the parent sulfoconjugate in female rats most likely explains why the female rat had lower drug exposure compared to male rat, as gender-related changes of sulfotransferase expression were widely reported in rats. The human liver S9 study suggests that gender-related pharmacokinetics of PF-02341066 are unlikely to occur in humans.
PF-02341066 是一种选择性的 c-Met/Alk 酪氨酸激酶抑制剂，目前正在临床开发中作为一种抗癌药物。在大鼠中的非临床毒代动力学评估显示，在给予相同剂量时，雄性大鼠的 PF-02341066 血浆浓度至少高出 2 倍，这与性别相关的药代动力学存在差异。一般来说，雄性大鼠比雌性大鼠中经历氧化代谢的药物的系统暴露较低，这归因于大鼠中 CYP 基因的性别特异性表达。了解为什么 PF-02341066 在大鼠中的性别相关药代动力学与一般观察结果相反，以及这种性别相关的药代动力学是否会在人类中出现，这可能会影响药物的疗效和毒性特征，这是很有趣的。使用 [(3)H]PF-02341066 在体外和体内研究了 PF-02341066 代谢的潜在性别相关差异。在雄性大鼠肝 S9 孵育物中发现氧化是主要的代谢途径，而磺化结合是雌性中的主要代谢途径。在人肝 S9 孵育物中，PF-02341066 的代谢产物谱没有定性差异。在雄性大鼠中，放射性的主要排泄途径是粪便，在雄性大鼠中，放射性的主要成分是母体药物（剂量的 29%），而在雌性大鼠中，放射性的主要成分是母体硫酸盐（剂量的 44%）。在雌性大鼠中更广泛地形成母体磺化结合物，这很可能解释了为什么雌性大鼠的药物暴露量低于雄性大鼠，因为性别相关的磺基转移酶表达变化在大鼠中广泛报道。人肝 S9 研究表明，PF-02341066 的性别相关药代动力学不太可能在人类中发生。
