The evaluation of individual variability in endogenous drugs’ metabolism and disposition is a very challenging task. We developed and validated a metabotype to pharmacokinetics (PK) matching approach by taking cholic acid as an example to predict the individualized PK of endogenous drugs. The stable isotope-labeled cholic acid was selected as the substitute analyte of cholic acid to ensure the accurate measurement of blood concentration. First, large-scale metabolite profiling studies were performed on the predose urine samples of 28 rats. Then, to examine the individualized PK of deuterium 4-cholic acid (d₄-cholic acid) in these rats, we determined its plasma concentrations and calculated the differential AUC values. Subsequently, we conducted a two-stage partial least-squares analysis in which 31 baseline metabolites were screened initially for predicting the individualized AUC values of d₄-cholic acid using the data of predose urine metabolites. Finally, network biology analysis was applied to give the biological interpretation of the individual variances in cholic acid metabolism and disposition, and the result further narrowed the selection of baseline metabolites from 31 to 2 (sarcosine and S-adenosyl-l-homocysteine) for such prediction. Collectively, this pharmacometabolomics research provided a new strategy for predicting individualized PK of endogenous drugs.

中文翻译：

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内源性药物中的药代动力学：预测胆酸个体化药代动力学的新方法

评价内源性药物代谢和处置的个体变异性是一项非常具有挑战性的任务。我们以胆酸为例来预测内源性药物的个体化PK，从而开发并验证了代谢型与药代动力学（PK）匹配的方法。选择稳定同位素标记的胆酸作为胆酸的替代分析物，以确保准确测量血药浓度。首先，对28只大鼠的服药前尿液样本进行了大规模代谢物谱分析研究。然后，检查氘化4-胆酸（d ₄-胆酸）中，我们确定了它们的血浆浓度并计算了差分AUC值。随后，我们进行了两阶段的局部最小二乘分析，其中初步筛选了31种基线代谢物，以使用服药前尿液代谢物的数据预测d _4-胆酸的个体化AUC值。最后，施加网络生物学分析，得到在胆酸代谢和处置的各个方差的生物学解释，结果进一步缩小基线代谢物从31到2（肌氨酸和选择小号-adenosyl-升-homocysteine）进行此类预测。总的来说，这项药代代谢研究为预测​​内源性药物的个体化PK提供了新的策略。