Tumor penetration of gefitinib (Iressa), an epidermal growth factor receptor tyrosine kinase inhibitor
Tumor penetration of gefitinib (Iressa), an epidermal growth factor receptor tyrosine kinase inhibitor
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DOI：
10.1158/1535-7163.mct-04-0329
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发表时间：
2005-04-01
影响因子：
5.7
通讯作者：
Stephens, TC
中科院分区：
文献类型：
--
作者：
McKillop, D;Partridge, EA;Stephens, TC
在口服（50 mg/kg） [C-14]-吉非替尼后，研究了吉非替尼相关物质在移植s.c.人肿瘤裸鼠和原位大鼠肺肿瘤模型中的相对分布。通过液体闪烁计数检测选定的组织样本的放射性，而通过高效液相色谱串联质谱检测检测血浆和肿瘤提取物及其主要代谢物（M523595和M537194）。组织分布也通过全身放射自显影确定。吉非替尼广泛分布在荷瘤小鼠的组织中，未改变的吉非替尼显示出大部分的肿瘤放射性。吉非替尼在小鼠s.c.肿瘤异种移植物中的浓度与皮肤浓度相似，并且比血浆浓度高得多（根据浓度-时间曲线下面积高达12倍）。原位大鼠肺肿瘤中吉非替尼相关物质的浓度与健康肺组织中的浓度相似，且远高于相应的血液水平。乳腺癌患者口服吉非替尼（易瑞沙）250 mg/d治疗>= 14天后，乳腺肿瘤组织中吉非替尼浓度（平均7.5 μ g/g, 16.7 μ mol/L）比血浆浓度高42倍，证实了吉非替尼在临床情况下优先由血液向肿瘤组织分布。这些吉非替尼肿瘤浓度远高于报道中在表皮生长因子受体突变型（0.2 μ mol/L）和野生型细胞（2 μ mol/L）中完全抑制表皮生长因子受体自磷酸化所需的体外浓度。
The relative distribution of gefitinib-related material in nude mice bearing s.c. human tumor xenografts and in an orthotopic rat lung tumor model was investigated following oral administration (50 mg/kg) of [C-14]-gefitinib. Selected tissue samples were monitored for radioactivity by liquid scintillation counting, whereas plasma and tumor extracts were assayed for gefitinib and its major metabolites (M523595 and M537194) by high-performance liquid chromatography with tandem mass spectrometric detection. Tissue distribution was also determined by whole body autoradiography. Gefitinib was extensively distributed into the tissues of tumor-bearing mice and unchanged gefitinib was shown to account for most of the tumor radioactivity. Concentrations of gefitinib in mouse s.c. tumor xenografts were similar to skin concentrations and substantially greater (up to 12-fold based on area under the concentration-time curve) than plasma. Concentrations of gefitinib-related material in an orthotopic rat lung tumor were similar to those in healthy lung tissue and were much higher than corresponding blood levels. Following treatment of breast cancer patients with oral gefitinib (Iressa) 250 mg/d for >= 14 days, gefitinib concentrations (mean, 7.5 mu g/g, 16.7 mu mol/L) in breast tumor tissue were 42 times higher than plasma, confirming the preferential distribution of gefitinib from blood into tumor tissue in the clinical situation. These gefitinib tumor concentrations are considerably higher than those reportedly required in vitro to achieve complete inhibition of epidermal growth factor receptor autophosphorylation in both epidermal growth factor receptor mutant (0.2 mu mol/L) and wild-type cells (2 mu mol/L).