Circadian regulation of transporter expression and implications for drug disposition

Introduction: Solute Carrier (SLC) and ATP-binding cassette (ABC) transporters expressed in the intestine, liver, and kidney determine the absorption, distribution, and excretion of drugs. In addition, most molecular and cellular processes show circadian rhythmicity controlled by circadian clocks that leads to diurnal variations in the pharmacokinetics and pharmacodynamics of many drugs and affects their therapeutic efficacy and toxicity. Area covered: This review provides an overview of the current knowledge on the circadian rhythmicity of drug transporters and the molecular mechanisms of their circadian control. Evidence for coupling drug transporters to circadian oscillators and the plausible candidates conveying circadian clock signals to target drug transporters, particularly transcription factors operating as the output of clock genes, is discussed. Expert opinion: The circadian machinery has been demonstrated to interact with the uptake and efflux of various drug transporters. The evidence supports the concept that diurnal changes that affect drug transporters may influence the pharmacokinetics of the drugs. However, more systematic studies are required to better define the timing of pharmacologically important drug transporter regulation and determine tissue- and sex-dependent differences. Finally, the transfer of knowledge based on the results and conclusions obtained primarily from animal models will require careful validation before it is applied to humans.

**引言**：肠道、肝脏与肾脏中表达的溶质载体（Solute Carrier, SLC）与ATP结合盒（ATP-binding cassette, ABC）转运蛋白，决定了药物的吸收、分布与排泄过程。此外，绝大多数分子与细胞过程均受昼夜节律钟调控，呈现出昼夜节律性，这会导致众多药物的药代动力学与药效动力学出现日间差异，并影响其治疗效果与毒性反应。

**论述范围**：本综述对当前关于药物转运蛋白昼夜节律性及其昼夜调控分子机制的研究认知进行了系统性概述。本文还探讨了将药物转运蛋白与昼夜节律振荡器相耦合的相关证据，以及将昼夜节律钟信号传递至靶标药物转运蛋白的潜在候选因子，尤其是作为时钟基因下游输出通路的转录因子。

**专家观点**：现已证实，昼夜节律系统可与多种药物转运蛋白的摄取与外排过程相互作用。现有研究证据支持如下观点：影响药物转运蛋白的日间变化可能会改变药物的药代动力学特征。然而，仍需开展更多系统性研究，以更精准地明确具有药理学重要性的药物转运蛋白调控的时间节点，并阐明其组织依赖性与性别依赖性差异。最后，基于主要来自动物模型的研究结果与结论所获得的相关知识，在应用于人类之前仍需进行严格的验证。