Transporters are divided into the ABC and SLC super-families, mediating the cellular efflux and influx of various xenobiotic and endogenous substrates. Here, an extensive literature search was performed to identify in vivo probe substrates for P-gp, BCRP and OAT1/3. For other transporters (e.g. OCT, OATP), no in vivo probe substrates could be identified from the available literature. Human kinetic data (Cmax, clearance, AUC) were extracted from 142 publications and Bayesian meta-analyses were performed using a hierarchical model to derive variability distributions and related uncertainty factors (UFs). For P-gp, human variability indicated that the kinetic default UF (3.16) would cover over 97.5% of healthy individuals, when considering the median value, while the upper confidence interval is exceeded. For BCRP and OAT1/3 human variability indicated that the default kinetic UF would not be exceeded while considering the upper confidence interval. Although limited kinetic data on transporter polymorphisms were available, inter-phenotypic variability for probe substrates was reported, which may indicate that the current default kinetic UF may be insufficient to cover such polymorphisms. Overall, it is recommended to investigate human genetic polymorphisms across geographical ancestry since they provide more robust surrogate measures of genetic differences compared to geographical ancestry alone. This analysis is based on pharmaceutical probe substrates which are often eliminated relatively fast from the human body. The transport of environmental contaminants and food-relevant chemicals should be investigated to broaden the chemical space of this analysis and assess the likelihood of potential interactions with transporters at environmental concentrations.

中文翻译：

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与化学危险性评估的不确定性因素相关的人潮和外排转运蛋白的变异性。

转运蛋白分为ABC和SLC超家族，介导各种外源性和内源性底物的细胞外排和流入。在这里，进行了广泛的文献检索以鉴定体内探针底物的P-gp，BCRP和OAT1 / 3。对于其他转运蛋白（例如OCT，OATP），无法从现有文献中鉴定出体内探针底物。从142种出版物中提取了人体动力学数据（Cmax，清除率，AUC），并使用层次模型进行了贝叶斯荟萃分析，以得出变异性分布和相关的不确定性因子（UFs）。对于P-gp，人的可变性表明，考虑中值时，动力学默认UF（3.16）将覆盖超过97.5％的健康个体，而超过了上限置信区间。对于BCRP和OAT1 / 3，人为变异性表明在考虑上限置信区间时不会超过默认的动力学UF。尽管可获得关于转运蛋白多态性的有限动力学数据，但已报道了探针底物的表型间变异性，这可能表明当前的默认动力学UF可能不足以覆盖此类多态性。总体而言，建议研究跨地理祖先的人类遗传多态性，因为与单独的地理祖先相比，它们提供了更强大的遗传差异替代指标。该分析基于药物探针底物，这些底物通常会相对较快地从人体中清除。