Tonial Nicholas C, Bota Sarah E, Kang Yuguang, Muanda Flory T, Urquhart Bradley L, Weir Matthew A
Department of Physiology and Pharmacology, Western University, London, Ontario, Canada.
ICES, London, Ontario, Canada.
Pharmacotherapy. 2025 Jul;45(7):414-425. doi: 10.1002/phar.70032. Epub 2025 Jul 17.
Clinically relevant drug-drug interactions (DDIs) are a common cause of adverse drug reactions (ADRs). Hepatic organic anion transporting polypeptides (OATPs) have recently been studied for their role in DDIs. The commonly prescribed antihypertensive angiotensin receptor blockers (ARBs) are known to be eliminated by hepatic OATPs. ARBs are commonly prescribed to patients with reduced kidney function, and kidney disease can result in profound changes to nonrenal drug elimination through reduced hepatic drug transport-mediated excretion. The antibiotic clarithromycin inhibits OATP activity whereas azithromycin does not, making them useful comparators to study DDIs with OATP substrate drugs.
To investigate whether co-prescription of ARBs and clarithromycin results in increased adverse events compared to azithromycin and whether kidney function modifies this risk.
We conducted a retrospective population-based cohort study in Ontario, Canada (2010-2021) using linked health care data for 106,322 older individuals (≥66 years) receiving an OATP substrate ARB (candesartan, olmesartan, telmisartan, valsartan) and newly co-prescribed clarithromycin (n = 32,693) or azithromycin (n = 73,629). Primary outcomes were hospital admissions or emergency department visits for hyperkalemia or acute kidney injury (AKI) within 14 days of antibiotic prescription. Adjusted risk ratios (aRR) were obtained using modified Poisson regression after controlling for eight potential confounders. Pre-specified effect measure modification analysis evaluated whether kidney function influenced these outcomes.
Compared to those co-prescribed azithromycin, patients receiving clarithromycin had a significantly higher risk of hyperkalemia (aRR 2.05, 95% confidence interval (CI) 1.32-3.18) and AKI (aRR 1.75, 95% CI 1.41-2.17). The risk of hyperkalemia increased as kidney function declined (multiplicative interaction; p = 0.01).
This population-based retrospective cohort study provides evidence of OATP-mediated drug interactions between ARBs and clarithromycin that warrants further investigation to guide clinical practice, especially for patients with reduced kidney function.
具有临床相关性的药物相互作用（DDIs）是药物不良反应（ADRs）的常见原因。肝脏有机阴离子转运多肽（OATPs）最近因其在药物相互作用中的作用而受到研究。众所周知，常用的降压药血管紧张素受体阻滞剂（ARBs）通过肝脏OATPs消除。ARBs常用于肾功能减退的患者，而肾脏疾病可通过减少肝脏药物转运介导的排泄导致非肾脏药物消除发生深刻变化。抗生素克拉霉素会抑制OATP活性，而阿奇霉素则不会，这使得它们成为研究与OATP底物药物发生药物相互作用的有用对照物。
研究与阿奇霉素相比，联合使用ARBs和克拉霉素是否会导致不良事件增加，以及肾功能是否会改变这种风险。
我们在加拿大安大略省进行了一项基于人群的回顾性队列研究（2010 - 2021年），使用了106322名年龄较大（≥66岁）接受OATP底物ARB（坎地沙坦、奥美沙坦、替米沙坦、缬沙坦）且新联合使用克拉霉素（n = 32693）或阿奇霉素（n = 73629）的个体的关联医疗数据。主要结局是抗生素处方后14天内因高钾血症或急性肾损伤（AKI）住院或就诊于急诊科。在控制了八个潜在混杂因素后，使用修正的泊松回归获得调整后的风险比（aRR）。预先设定的效应量修正分析评估肾功能是否会影响这些结局。
与联合使用阿奇霉素的患者相比，接受克拉霉素的患者发生高钾血症的风险显著更高（aRR 2.05，95%置信区间（CI）1.32 - 3.18）和AKI（aRR 1.75，95% CI 1.41 - 2.17）。高钾血症的风险随着肾功能下降而增加（相乘交互作用；p = 0.01）。
这项基于人群的回顾性队列研究提供了ARBs和克拉霉素之间存在OATP介导的药物相互作用的证据，这值得进一步研究以指导临床实践，特别是对于肾功能减退的患者。
