探索之间的关系表达细胞色素P450酶和吉非替尼药物动力学。

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Swaisland HC, Cantarini MV,富R,霍尔特

探索之间的关系表达细胞色素P450酶和吉非替尼药物动力学。

45 Pharmacokinet。2006; (6): 633 - 44。doi: 10.2165 / 00003088-200645060-00006。

PubMed ID

16719544 (在PubMed

]

文摘

背景和目的:暴露于吉非替尼(艾瑞莎ZD1839)、表皮生长因子受体酪氨酸激酶抑制剂,是学科之间高度可变。为了解释这种变化,三药代动力学研究在健康的志愿者进行调查之间的关系接触吉非替尼和细胞色素P450 (CYP) 3一个表型(研究1),CYP3A5基因型(研究2)和CYP2D6基因型(研究3)。方法:在研究1所有15名健康志愿者接受单一口服剂量咪达唑仑(7.5毫克),CYP3A探测器,和吉非替尼(500毫克),由一个适当的洗脱期。咪达唑仑和吉非替尼的血浆浓度测定。在研究2中,73名健康志愿者与之前定义的单剂吉非替尼药代动力学资料CYP3A5基因分型。在研究单剂量口服3吉非替尼(250毫克)管理CYP2D6贫穷和广泛metabolisers在每组(n = 15)。吉非替尼的血浆浓度及其主要代谢物,M523595,测量。吉非替尼的血浆浓度,M523595和咪达唑仑测量用高性能液相色谱串联质谱检测,和适当的药代动力学参数测定non-compartmental方法。CYP2D6 CYP3A5基因分析(研究2)和(3)研究等位基因进行了使用标准的方法。结果:在研究1之间的相关性有迹象表明血浆浓度时间曲线下的面积从时间0到无穷大(AUCinfinity)咪达唑仑和吉非替尼的价值观,虽然这没有达到统计学意义(p = 0.062,回归分析)。在研究2 8 73名志愿者(11%)被确定为CYP3A5表达者。 No apparent relationship was observed between the occurrence of the CYP3A5 expresser genotype and gefitinib plasma clearance or terminal elimination halflife. In study 3 M523595 was not detected in any plasma samples collected from poor CYP2D6 metabolisers. Gefitinib geometric mean AUCinfinity and peak plasma drug concentration were higher in poor CYP2D6 metabolisers compared with extensive metabolisers (AUCinfinity 3060 vs 1430 ng . h/mL, p < 0.05, ANOVA), although the range of values was wide with considerable overlap between the groups. Gefitinib was well tolerated in both groups. CONCLUSIONS: Individual differences in CYP3A expression do not explain all the interindividual variability in gefitinib exposure. There is no apparent relationship between CYP3A5 genotype and gefitinib clearance. The lack of measurable levels of M523595 in poor CYP2D6 metabolisers confirms that production of this metabolite is mediated by CYP2D6. Although higher exposure to gefitinib occurs in individuals who are poor CYP2D6 metabolisers, genotyping prior to initiation of therapy and dosage adjustment are not warranted.

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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