PREDICTION OF DRUG INTERACTIONS IN VIVO AND IN VITRO

体内和体外药物相互作用的预测

• 批准号: 6240431
• 负责人: WILLIAM F TRAGER
• 金额: $ 18.58万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-01 至 1998-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6240431
• 关键词: blood chemistry; carbamazepine; cytochrome P450; drug interactions; drug metabolism; enzyme activity; enzyme inhibitors; fluconazole; human subject; liver metabolism; microsomes; pharmacokinetics; phenobarbital; phenytoin; protein isoforms; pyrrolidinediones; urinalysis; warfarin

The overall objective of this proposal is to evaluate a new framework for the prediction of inhibition based drug interactions. This framework is based on the ability to characterize the effects of inhibitors on specific cytochrome P450 isoforms using human liver microsomal preparations. Two hypotheses will be tested: Hypothesis 1: The mechanism of any drug-inhibitor in vivo interaction can be accounted for from (i) a determination of the specific cytochrome P450 isoforms responsible for that drug's major route of metabolism and (ii) a measurement of the inhibitor in vitro Ki for each isoform. Hypothesis 2: For any drug-inhibitor in vivo interaction, the Michaelis-Menton model can be used to calculate an isoform specific in vivo inhibition constant (Kiiv). This constant provides a quantitative estimate of the magnitude of interaction to be expected between that inhibitor and any substrate. These hypotheses will be evaluated with two classes of drugs for which inhibition based interactions constitute a critical clinical reality. The following Specific Aims will be pursued: 1(a) To determine, using human liver microsomes, if the clinical interactions between warfarin and 13 commonly prescribed drugs are a consequence of the inhibition of CYP2C9. 1(b) To determine, using human liver microsomes, if the clinical interactions between 4 major anticonvulsants and 33 other drugs are a consequence of inhibition of the specific isoforms responsible for the major fractional clearances of the anticonvulsants. If they are, to determine the in vitro Ki's for the inhibition of these isoforms and to compare these values to the corresponding Kiiv's estimated from literature data. 2(a) To demonstrate, for isoform CYP2C9, that (i) the degree of interaction between (S)-warfarin and fluconazole can be predicted quantitatively by the ratio, I/Kiiv, where I is the plasma inhibitor concentration and (ii) the same Kiiv for 2C9 is obtained for fluconazole when phenytoin is used as the substrate. 2(b) To demonstrate, for isoform 3A4, that (i) the degree of interaction between (R)-warfarin and fluconazole can be predicted quantitatively by the ratio, I/Kiiv, and (ii) the same Kiiv for 3A4 is obtained for fluconazole when carbamazepine is used as the substrate. 2(c) To demonstrate that the approach of specific aims 2(a) and 2(b) is inhibitor independent, a second inhibitor will be used with the same substrates for each isozyme. The experimental approaches include the use of human liver bank, reliable analytical techniques and a number of human studies in healthy subjects. If the proposed hypotheses are validated it will become possible to predict inhibition based interactions for any new drug.

该提案的总体目的是评估一个新框架 基于抑制药物相互作用的预测。 这个框架是 基于表征抑制剂对 使用人肝微粒体的特定细胞色素P450同工型 准备。 将检验两个假设：假设1： 任何药物抑制剂在体内相互作用的机制都可以解释 从（i）确定特定的细胞色素P450同工型 负责该药物的主要新陈代谢途径和（ii） 测量每个同工型的抑制剂在体外Ki中的测量。 假设 2：对于任何药物抑制剂体内相互作用，Michaelis-Menton 模型可用于计算同工型特异性体内抑制 常数（kiiv）。 这个常数提供了对 该抑制剂和任何人之间的相互作用大小 基材。 这些假设将通过两类药物进行评估 基于抑制作用的相互作用构成了关键的临床现实。 将追求以下具体目标：1（a）确定，使用 人肝微粒体，如果华法林和 13通常处方药是抑制的结果 CYP2C9。 1（b）使用人肝微粒体确定，如果临床 4种主要抗惊厥药与其他33种药物之间的相互作用是A 抑制特定同工型的结果 抗惊厥药的主要分数清除。 如果是， 确定抑制这些同工型的体外Ki和 将这些值与相应的Kiiv估计的值进行比较 文献数据。 2（a）要证明，对于同工型CYP2C9，（i） （S） - 华尔法林和氟康唑之间的相互作用程度可以是 按比例定量预测，i/kiiv，我是等离子体 抑制剂浓度和（ii）获得2C9的相同KIIV 氟康唑当苯妥英钠用作底物时。 2（b）至 证明，对于同工型3A4，（i）（i） （R） - 华法林和氟康唑可以通过定量预测 比率，I/KIIV和（ii）氟康唑的3A4获得了相同的KIIV 当使用卡马西平用作底物时。 2（c）证明 特定目的的方法2（a）和2（b）是抑制剂独立的，a 第二个抑制剂将用于每个同工酶的相同底物。 实验方法包括使用人肝库，可靠 在健康受试者中的分析技术和许多人类研究。 如果提出的假设得到了验证，将有可能 预测基于任何新药的基于抑制作用的相互作用。