Anlotinib is a new oral tyrosine kinase inhibitor; this study was designed to characterize its pharmacokinetics and disposition. Anlotinib was evaluated in rats, tumor-bearing mice, and dogs and also assessed in vitro to characterize its pharmacokinetics and disposition and drug interaction potential. Samples were analyzed by liquid chromatography/mass spectrometry. Anlotinib, having good membrane permeability, was rapidly absorbed with oral bioavailability of 28%-58% in rats and 41%-77% in dogs. Terminal half-life of anlotinib in dogs (22.8±11.0 h) was longer than that in rats (5.1±1.6 h). This difference appeared to be mainly associated with an interspecies difference in total plasma clearance (rats, 5.35±1.31 L·h^-1·kg^-1; dogs, 0.40±0.06 L·h^-1/kg^-1). Cytochrome P450-mediated metabolism was probably the major elimination pathway. Human CYP3A had the greatest metabolic capability with other human P450s playing minor roles. Anlotinib exhibited large apparent volumes of distribution in rats (27.6±3.1 L/kg) and dogs (6.6±2.5 L/kg) and was highly bound in rat (97%), dog (96%), and human plasma (93%). In human plasma, anlotinib was predominantly bound to albumin and lipoproteins, rather than to α₁-acid glycoprotein or γ-globulins. Concentrations of anlotinib in various tissue homogenates of rat and in those of tumor-bearing mouse were significantly higher than the associated plasma concentrations. Anlotinib exhibited limited in vitro potency to inhibit many human P450s, UDP-glucuronosyltransferases, and transporters, except for CYP3A4 and CYP2C9 (in vitro half maximum inhibitory concentrations, <1 μmol/L). Based on early reported human pharmacokinetics, drug interaction indices were 0.16 for CYP3A4 and 0.02 for CYP2C9, suggesting that anlotinib had a low propensity to precipitate drug interactions on these enzymes. Anlotinib exhibits many pharmacokinetic characteristics similar to other tyrosine kinase inhibitors, except for terminal half-life, interactions with drug metabolizing enzymes and transporters, and plasma protein binding.

中文翻译：

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口服酪氨酸激酶抑制剂anlotinib在实验动物中的药代动力学和处理。

Anlotinib是一种新型的口服酪氨酸激酶抑制剂。本研究旨在表征其药代动力学和性状。在大鼠，荷瘤小鼠和狗中评估了安洛替尼，并在体外进行了评估，以表征其药代动力学，性状和药物相互作用潜力。通过液相色谱/质谱法分析样品。具有良好的膜通透性的安洛替尼迅速吸收，大鼠的口服生物利用度为28％-58％，狗的口服生物利用度为41％-77％。狗的阿洛替尼终末半衰期（22.8±11.0 h）长于大鼠（5.1±1.6 h）。这种差异似乎主要与种间总血浆清除率的差异有关（大鼠为5.35±1.31 L·h ^-1 ·kg ^-1；狗为0.40±0.06 L·h ^-1 / kg^-1）。细胞色素P450介导的代谢可能是主要的消除途径。人CYP3A具有最大的代谢能力，而其他人P450则起次要作用。安乐替尼在大鼠（27.6±3.1 L / kg）和狗（6.6±2.5 L / kg）中表现出较大的表观分布量，并在大鼠（97％），狗（96％）和人血浆（93％）中高度结合）。在人血浆中，anlotinib主要被结合到白蛋白和脂蛋白，而不是α ₁酸糖蛋白或γ-球蛋白。大鼠和荷瘤小鼠的各种组织匀浆中的anlotinib浓度均显着高于相关的血浆浓度。除了CYP3A4和CYP2C9（体外半数最大抑制浓度，<1μmol/ L）外，安洛替尼在体外抑制许多人类P450，UDP-葡萄糖醛酸转移酶和转运蛋白的能力有限。根据早期报道的人类药代动力学，CYP3A4的药物相互作用指数为0.16，而CYP2C9的药物相互作用指数为0.02，这表明安洛替尼在这些酶上具有促进药物相互作用的倾向。除了终末半衰期，与药物代谢酶和转运蛋白的相互作用以及血浆蛋白结合以外，安洛替尼还具有许多与其他酪氨酸激酶抑制剂相似的药代动力学特征。