药代动力学的药物相互作用与利福平吉非替尼,伊曲康唑和美托洛尔。

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Swaisland HC,史密斯Ranson M, RP,利百特J, Laight, McKillop D,野生乔丹

药代动力学的药物相互作用与利福平吉非替尼,伊曲康唑和美托洛尔。

Pharmacokinet。2005; 44 (10): 1067 - 81。doi: 10.2165 / 00003088-200544100-00005。

PubMed ID

16176119 (在PubMed

]

文摘

背景和目的:吉非替尼(艾瑞莎ZD1839)、表皮生长因子受体酪氨酸激酶抑制剂,已在多个国家批准用于治疗晚期非小细胞肺癌。进行了临床前研究确定细胞色素P450 (CYP)同功酶参与代谢的吉非替尼和评估潜在的吉非替尼通过抑制CYP同功酶引起药物相互作用。基于这些发现,三个临床研究进行调查与吉非替尼体内药代动力学药物的相互作用。方法:在临床前研究放射性标记与吉非替尼孵化:(i)肝微粒体蛋白选择性CYP抑制剂的存在;(2)表达了CYP酶。人肝微粒体蛋白与选择性CYP孵化基质在吉非替尼的存在。临床研究都是第一阶段,非盲、只有研究;两人一个随机、双向交叉设计和第三nonrandomised。第一次和第二次的药物动力学研究调查吉非替尼的一个强有力的CYP3A4诱导物(利福平(利福平))或抑制剂(伊曲康唑)在健康男性志愿者。第三个研究调查了吉非替尼对药物动力学的影响美托洛尔,CYP2D6衬底,固体肿瘤患者。 RESULTS: The results of preclinical studies demonstrated that CYP3A4 is involved in the metabolism of gefitinib and that gefitinib is a weak inhibitor of CYP2D6 activity. In clinical studies when gefitinib was administered in the presence of rifampicin, geometric mean (gmean) maximum concentration and area under the plasma concentration-time curve (AUC) were reduced by 65% and 83%, respectively; these changes were statistically significant. When gefitinib was administered in the presence of itraconazole, gmean AUC increased by 78% and 61% at gefitinib doses of 250 and 500 mg, respectively; these changes also being statistically significant. Coadministration of metoprolol with gefitinib resulted in a 35% increase in the metoprolol area under plasma concentration-time curve from time zero to the time of the last quantifiable concentration; this change was not statistically significant. There was no apparent change in the safety profile of gefitinib as a result of coadministration with other agents. CONCLUSIONS: Although CYP3A4 inducers may reduce exposure to gefitinib, further work is required to define any resultant effect on the efficacy of gefitinib. Exposure to gefitinib is increased by coadministration with CYP3A4 inhibitors, but since gefitinib is known to have a good tolerability profile, a dosage reduction is not recommended. Gefitinib is unlikely to exert a clinically relevant effect on the pharmacokinetics of drugs that are dependent on CYP2D6-mediated metabolism for their clearance, but the potential to increase plasma concentrations should be considered if gefitinib is coadministered with CYP2D6 substrates that have a narrow therapeutic index or are individually dose titrated.

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药物酶

药物	酶	类	生物	药理作用	行动
吉非替尼	细胞色素P450 2 d6	蛋白质	人类	没有	底物 抑制剂	细节