Discipline of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, Flinders University College of Medicine and Public Health, Flinders University, Adelaide, Australia.
Certara, Princeton, NJ, USA; Centre for Medicines Use and Safety, Monash University, Melbourne, Australia.
Pharmacol Ther. 2023 Aug;248:108459. doi: 10.1016/j.pharmthera.2023.108459. Epub 2023 May 30.
Drug-drug interactions (DDIs) arising from the perturbation of drug metabolising enzyme activities represent both a clinical problem and a potential economic loss for the pharmaceutical industry. DDIs involving glucuronidated drugs have historically attracted little attention and there is a perception that interactions are of minor clinical relevance. This review critically examines the scope and aetiology of DDIs that result in altered exposure of glucuronidated drugs. Interaction mechanisms, namely inhibition and induction of UDP-glucuronosyltransferase (UGT) enzymes and the potential interplay with drug transporters, are reviewed in detail, as is the clinical significance of known DDIs. Altered victim drug exposure arising from modulation of UGT enzyme activities is relatively common and, notably, the incidence and importance of UGT induction as a DDI mechanism is greater than generally believed. Numerous DDIs are clinically relevant, resulting in either loss of efficacy or an increased risk of adverse effects, necessitating dose individualisation. Several generalisations relating to the likelihood of DDIs can be drawn from the known substrate and inhibitor selectivities of UGT enzymes, highlighting the importance of comprehensive reaction phenotyping studies at an early stage of drug development. Further, rigorous assessment of the DDI liability of new chemical entities that undergo glucuronidation to a significant extent has been recommended recently by regulatory guidance. Although evidence-based approaches exist for the in vitro characterisation of UGT enzyme inhibition and induction, the availability of drugs considered appropriate for use as 'probe' substrates in clinical DDI studies is limited and this should be a research priority.
药物-药物相互作用（DDI）源于药物代谢酶活性的改变，这既代表了临床问题，也对制药行业构成潜在的经济损失。涉及葡萄糖醛酸化药物的 DDI 历来受到较少关注，人们普遍认为这些相互作用的临床相关性较小。本综述批判性地考察了导致葡萄糖醛酸化药物暴露改变的 DDI 的范围和病因。详细回顾了相互作用机制，即 UDP-葡萄糖醛酸转移酶（UGT）酶的抑制和诱导，以及与药物转运体的潜在相互作用，还探讨了已知 DDI 的临床意义。由于 UGT 酶活性的调节而导致的受影响药物暴露的改变相对常见，值得注意的是，UGT 诱导作为 DDI 机制的发生率和重要性比普遍认为的要大。许多 DDI 具有临床相关性，导致疗效丧失或不良反应风险增加，需要个体化剂量。从 UGT 酶已知的底物和抑制剂选择性可以得出与 DDI 可能性相关的几个概括，突出了在药物开发的早期阶段进行全面的反应表型研究的重要性。此外，最近的监管指南建议对经历显著葡萄糖醛酸化的新化学实体的 DDI 易感性进行严格评估。尽管存在用于体外表征 UGT 酶抑制和诱导的基于证据的方法，但可用于临床 DDI 研究中作为“探针”底物的药物有限，这应该是一个研究重点。
