Rodieux Frédérique, Gotta Verena, Pfister Marc, van den Anker Johannes N
Pediatric Pharmacology, University of Basel Children's Hospital (UKBB), Basel, Switzerland.
Quantitative Solutions/Certara, Menlo Park, CA, USA.
J Clin Pharmacol. 2016 Jul;56 Suppl 7:S173-92. doi: 10.1002/jcph.721.
Drug transporters play a key role in mediating the uptake of endo- and exogenous substances into cells as well as their efflux. Therefore, variability in drug transporter activity can influence pharmaco- and toxicokinetics and be a determinant of drug safety and efficacy. In children, particularly in neonates and young infants, the contribution of tissue-specific drug transporters to drug absorption, distribution, and excretion may differ from that in adults. In this review 5 major factors and their interdependence that may influence drug transporter activity in children are discussed: developmental differences, genetic polymorphisms, pediatric comorbidities, interacting comedication, and environmental factors. Even if data are sparse, altered drug transporter activity due to those factors have been associated with clinically relevant differences in drug disposition, efficacy, and safety in pediatric patients. Single nucleotide polymorphisms in drug transporter-encoding genes were the most studied source of drug transporter variability in children. However, in the age group where drug transporter activity has been reported to differ from that in adults, namely neonates and young infants, hardly any studies have been performed. Longitudinal studies in this young population are required to investigate the age- and disease-dependent genotype-phenotype relationships and relevance of drug transporter drug-drug interactions. Physiologically based pharmacokinetic modeling approaches can integrate drug- and patient-specific parameters, including drug transporter ontogeny, and may further improve in silico predictions of pediatric-specific pharmacokinetics.
药物转运体在介导内源性和外源性物质进入细胞以及它们的外排过程中发挥着关键作用。因此，药物转运体活性的变异性会影响药物代谢动力学和毒代动力学，并且是药物安全性和有效性的一个决定因素。在儿童中，尤其是新生儿和幼儿，组织特异性药物转运体对药物吸收、分布和排泄的作用可能与成人不同。在这篇综述中，讨论了可能影响儿童药物转运体活性的5个主要因素及其相互依存关系：发育差异、基因多态性、儿科合并症、相互作用的合并用药以及环境因素。即使数据稀少，但由于这些因素导致的药物转运体活性改变已与儿科患者药物处置、疗效和安全性的临床相关差异相关联。药物转运体编码基因中的单核苷酸多态性是儿童药物转运体变异性研究最多的来源。然而，在据报道药物转运体活性与成人不同的年龄组，即新生儿和幼儿中，几乎没有进行任何研究。需要在这个年轻人群中进行纵向研究，以调查年龄和疾病依赖性的基因型-表型关系以及药物转运体药物-药物相互作用的相关性。基于生理学的药代动力学建模方法可以整合药物和患者特异性参数，包括药物转运体的个体发育，并可能进一步改善儿科特异性药代动力学的计算机模拟预测。
