Which concentration of the inhibitor should be used to predict in vivo drug interactions from in vitro data?
Which concentration of the inhibitor should be used to predict in vivo drug interactions from in vitro data?
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DOI：
10.1208/ps040425
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发表时间：
2002-01-01
期刊：
影响因子：
--
通讯作者：
Sugiyama, Y
中科院分区：
文献类型：
--
作者：
Ito, K;Chiba, K;Sugiyama, Y
当一种药物的代谢被另一种药物竞争性或非竞争性地抑制时，体内相互作用的程度可以从[i](U)/K(I)比值来评估，其中[i](U)是酶周围的游离浓度，K(I)是抑制剂的抑制常数。在本研究中，我们利用文献数据估计已知的细胞色素P450抑制剂或底物的[i](U)/K(I)比值，以循环血中抑制物的最大浓度([i](Max))、其在循环血中的最大未结合浓度([i](max，u))和其在肝脏入口处的最大未结合浓度([i](in，max，u))作为[i](U)，并将结果进行比较。为了计算[1]，/K(I)比值，从文献中获得了每种药物的药代动力学参数，以及它们在体外利用人肝微粒子测定的K(I)值。对于大多数计算的[I](In，max，u)/K(I)比值小于0.25的药物，约有一半的药物应用于所研究的药物，没有体内相互作用的报道或临床研究中没有相互作用的报道。相比之下，约90%和65%的药物的[i](max，u)/K(J)和[1](Max)/K(I)的比值分别小于0.25，约30%的联合用药药物的浓度-时间曲线下的面积报告增加了1.25倍以上。这些发现表明，与使用[i](in，max，u)值相比，当使用[i](max，u)或[i](Max)值时，低估体内相互作用的可能性(假阴性预测的可能性)更大。
When the metabolism of a drug is competitively or noncompetitively inhibited by another drug, the degree of in vivo interaction can be evaluated from the [I] (u)/K (i) ratio, where [I] (u) is the unbound concentration around the enzyme and K (i) is the inhibition constant of the inhibitor. In the present study, we evaluated the metabolic inhibition potential of drugs known to be inhibitors or substrates of cytochrome P450 by estimating their [I] (u)/K (i) ratio using literature data.The maximum concentration of the inhibitor in the circulating blood ([I] (max)), its maximum unbound concentration in the circulating blood ([I] (max,u)), and its maximum unbound concentration at the inlet to the liver ([I] (in,max,u)) were used as [I] (u), and the results were compared with each other. In order to calculate the [1], /K (i) ratios, the pharmacokinetic parameters of each drug were obtained from the literature, together with their reported K (i) values determined in in vitro studies using human liver microsomes.For most of the drugs with a calculated [I] (in,max,u) /K (i) ratio less than 0.25, which applied to about half of the drugs investigated, no in vivo interactions had been reported or "no interaction" was reported in clinical studies. In contrast, the [I] (max,u)/K (j) and [1] (max)/K (i) ratio was calculated to be less than 0.25 for about 90% and 65% of the drugs, respectively, and more than a 1.25-fold increase was reported in the area under the concentration-time curve of the co-administered drug for about 30% of such drugs. These findings indicate that the possibility of underestimation of in vivo interactions (possibility of false-negative prediction) is greater when [I] (max,u) or [I] (max) values are used compared with using [I] (in,max,u) values.