Min Jee Sun, Jo Seong Jun, Lee Sangyoung, Kim Duk Yeon, Kim Da Hyun, Lee Chae Bin, Bae Soo Kyung
College of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea, Bucheon, 14662, Republic of Korea.
Department of Pharmaceutical Sciences, State University of New York, Buffalo, NY, 14214, USA.
Drug Des Devel Ther. 2025 Apr 30;19:3509-3537. doi: 10.2147/DDDT.S506957. eCollection 2025.
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are peptide-derived analogs that were initially investigated to treat type 2 diabetes. Recently, a drug targeting the receptors of both GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) (tirzepatide) has been introduced to the market, and its indications have expanded to include treating obesity. Here, we review the pharmacokinetics, pharmacokinetic drug-drug interactions (DDIs), and pharmacokinetic modeling approaches of four currently available GLP-1 RAs (exenatide, liraglutide, dulaglutide, and semaglutide) and tirzepatide. To address the extremely short half-life (2 min) of native human GLP-1, structural modifications have been applied to GLP-1 RAs and a dual GLP-1/GIP RA. These include amino acid sequence substitutions, fatty acid conjugation using a linker, and fusion with albumin or the IgG fragment crystallizable (Fc) region, resulting in minimal metabolism and renal excretion. Due to their diverse structures, the pharmacokinetic profiles vary, and a prolonged half-life may be associated with an increased risk of adverse events. Clinically significant drug-metabolizing enzyme- and transporter-mediated DDIs are yet to be reported. Mechanism-of-action-mediated DDIs are currently limited to those involving delayed gastric emptying, and most studies have found them to be clinically insignificant. However, significant changes in exposure were observed for oral contraceptives and levothyroxine following the administration of tirzepatide and oral semaglutide, respectively, indicating the need for close monitoring in these instances. Thirty models have been developed to predict pharmacokinetics and physiologically based pharmacokinetic modeling can be useful for assessing mechanism-of-action-mediated DDIs. Alterations in the volume of distribution and clearance resulting from other mechanisms of action (eg, reduced fat mass, changes in cytochrome P450 activity, and glomerular filtration rate) are key factors in determining pharmacokinetics. However, the DDIs mediated by these factors remain poorly understood and require further investigation to ensure that GLP-1 RAs can be safely used with concomitant medications.
胰高血糖素样肽-1受体激动剂（GLP-1 RAs）是肽衍生的类似物，最初被研究用于治疗2型糖尿病。最近，一种同时靶向GLP-1和葡萄糖依赖性促胰岛素多肽（GIP）受体的药物（替尔泊肽）已投放市场，其适应症已扩大到包括治疗肥胖症。在此，我们综述了四种目前可用的GLP-1 RAs（艾塞那肽、利拉鲁肽、度拉鲁肽和司美格鲁肽）以及替尔泊肽的药代动力学、药代动力学药物-药物相互作用（DDIs）和药代动力学建模方法。为了解决天然人GLP-1极短的半衰期（2分钟）问题，已对GLP-1 RAs和双GLP-1/GIP RA进行了结构修饰。这些修饰包括氨基酸序列替换、使用连接子进行脂肪酸缀合以及与白蛋白或免疫球蛋白G（IgG）可结晶片段（Fc）区域融合，从而使代谢和肾排泄降至最低。由于它们结构多样，药代动力学特征各不相同，半衰期延长可能与不良事件风险增加有关。尚未有临床显著的药物代谢酶和转运体介导的DDIs报道。作用机制介导的DDIs目前仅限于那些涉及胃排空延迟的情况，大多数研究发现它们在临床上无显著意义。然而，分别在给予替尔泊肽和口服司美格鲁肽后，观察到口服避孕药和左甲状腺素的暴露量有显著变化，这表明在这些情况下需要密切监测。已经开发了30种模型来预测药代动力学，基于生理学的药代动力学建模可用于评估作用机制介导的DDIs。由其他作用机制（如脂肪量减少、细胞色素P450活性变化和肾小球滤过率）导致的分布容积和清除率改变是决定药代动力学的关键因素。然而，由这些因素介导的DDIs仍知之甚少，需要进一步研究以确保GLP-1 RAs能与伴随药物安全联用。
