总体框架的预测口服药物相互作用引起的CYP3A4从体内诱导信息。

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Ohno Y, Hisaka,上野M,铃木H

总体框架的预测口服药物相互作用引起的CYP3A4从体内诱导信息。

Pharmacokinet。2008; 47 (10): 669 - 80。doi: 10.2165 / 00003088-200847100-00004。

PubMed ID

18783297 (在PubMed

]

文摘

背景:诱导细胞色素P450 (CYP) 3 a4潜在底物药物的血药浓度降低到少于十分之一,从而导致无效的药物治疗。虽然药物之间的相互作用的预测(ddi)由感应CYP3A4的主要表现的基础上,在体外信息,这种方法已经会见了有限的成功的准确性和适用性。因此,一个现实的方法预测CYP3A4-mediated归纳ddi是主要的临床重要性。摘要目的:本研究的目的是构建一个健壮的、准确的预测方法CYP3A4-mediated归纳ddi。这种方法开发原则的基础上申请预测抑制ddi的以前的报告。这一原则的一个独特的性格是改变程度的血浆浓度时间曲线下的面积(AUC)是预测的基础上,从最小的临床研究不使用体内信息体外数据。方法:分析是基于42 DDI研究人类在37在1983 - 2007年期间发表文章。动力学分析表明,减少产生的AUC CYP3A4的基底连续政府诱导物的CYP3A4方程可以近似的1 / (1 + CRCYP3A4 * ICCYP3A4),在CRCYP3A4 CYP3A4的明显贡献比口服间隙的底物和ICCYP3A4明显增加间隙CYP3A4的底物产生的感应。用这个方程,计算ICCYP3A4七抗病诱导剂(吡格列酮苯妥英、卡马西平,应用波生坦依法韦伦,利福平(利福平),和圣约翰草(金丝桃属植物))的基础上减少的AUC coadministered CYP3A4的标准衬底,如辛伐他汀、十DDI的研究。CRCYP3A4计算了22基板的基础上,从抑制DDI之前报道的方法研究使用强有力的CYP3A4抑制剂如伊曲康唑或酮康唑。 RESULTS: The proposed method enabled the prediction of AUC reduction by CYP3A4 induction with any combination of these substrates and inducers (total 154 matches). To assess the accuracy of the prediction, the AUC reductions in 32 studies were analysed. We found that the magnitude of the deviation between the mean values of the observed and predicted AUCs of all substrate drugs was <20% of the AUCs of the respective substrate drugs before administration of the inducers. In addition, rifampicin was found to be the most potent inducer among the compounds analysed in the present study, with an ICCYP3A4 value of 7.7, followed by phenytoin and carbamazepine, with values of 4.7 and 3.0, respectively. The ICCYP3A4 values of the other CYP3A4 inducers analysed in the present study were approximately 1 or less, which suggests that the AUCs of coadministered drugs may not be reduced to less than approximately half, even if the drug is metabolized solely by CYP3A4. CONCLUSION: By using the method reported in the present study, the susceptibilities of a substrate drug of CYP3A4 to inductive DDIs can be predicted quantitatively. It was indicated that coadministration of rifampicin, phenytoin and carbamazepine may reduce plasma AUCs to less than half for a broad range of CYP3A4 substrate drugs, with CRCYP3A4 values greater than 0.13, 0.21 and 0.33, respectively.

beplay体育安全吗DrugBank数据引用了这篇文章

药物酶

药物	酶	类	生物	药理作用	行动
Fosphenytoin	细胞色素P450 3 a4	蛋白质	人类	未知的	底物 诱导物	细节
苯妥英	细胞色素P450 3 a4	蛋白质	人类	没有	底物 诱导物	细节