Understanding drug-drug interaction and pharmacogenomic changes in pharmacokinetics for metabolized drugs
Understanding drug-drug interaction and pharmacogenomic changes in pharmacokinetics for metabolized drugs
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DOI：
10.1007/s10928-019-09626-7
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发表时间：
2019-04-01
影响因子：
2.5
通讯作者：
Sodhi, Jasleen K.
中科院分区：
文献类型：
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作者：
Benet, Leslie Z.;Bowman, Christine M.;Sodhi, Jasleen K.
在这里，我们描述和总结了药物相互作用和药物基因组学差异时代谢药物的药代动力学变化。在多次给药至稳定状态后，口服全身浓度-时间曲线似乎遵循单室体模型，具有较短的限速半衰期，通常明显短于单剂量终点半衰期。这种简化的稳态配置模型允许比较药物相互作用或药物基因组变异研究后的可测量参数（即曲线下面积、半衰期、最大浓度和达到最大浓度的时间），以表征药物是低还是高肝提取比，即使没有静脉给药。根据曲线下面积、最大浓度和半衰期的比值来确定药物的特征，并认识到药物相互作用和药物基因组变异研究的分布体积基本不变，其中只有代谢结果发生变化，转运体没有显着参与。比较单剂量相互作用后的最大浓度变化和药物基因组变异研究也可以确定肠道首次通过变化的意义。再次强调口服和静脉注射低肝提取比药物后蛋白质结合变化与药效学结果的不相关性，与高肝提取比药物的相关性。
Here we characterize and summarize the pharmacokinetic changes for metabolized drugs when drug-drug interactions and pharmacogenomic variance are observed. Following multiple dosing to steady-state, oral systemic concentration-time curves appear to follow a one-compartment body model, with a shorter rate limiting half-life, often significantly shorter than the single dose terminal half-life. This simplified disposition model at steady-state allows comparisons of measurable parameters (i.e., area under the curve, half-life, maximum concentration and time to maximum concentration) following drug interaction or pharmacogenomic variant studies to be utilized to characterize whether a drug is low versus high hepatic extraction ratio, even without intravenous dosing. The characteristics of drugs based on the ratios of area under the curve, maximum concentration and half-life are identified with recognition that volume of distribution is essentially unchanged for drug interaction and pharmacogenomic variant studies where only metabolic outcomes are changed and transporters are not significantly involved. Comparison of maximum concentration changes following single dose interaction and pharmacogenomic variance studies may also identify the significance of intestinal first pass changes. The irrelevance of protein binding changes on pharmacodynamic outcomes following oral and intravenous dosing of low hepatic extraction ratio drugs, versus its relevance for high hepatic extraction ratio drugs is re-emphasized.