School of Pharmaceutical Sciences of Ribeirão Preto, USP-São Paulo University, Ribeirão Preto, SP, Brazil.
Experimental Nephrology, Medicine Clinic D, University Hospital Münster, Münster, Germany.
J Clin Pharmacol. 2020 Aug;60(8):1076-1086. doi: 10.1002/jcph.1603. Epub 2020 Mar 9.
Gabapentin (GBP) is an organic cation mainly eliminated unchanged in urine, and active drug secretion has been suggested to contribute to its renal excretion. Our objective was to evaluate the potential drug-drug interaction between GBP and cetirizine (CTZ), an inhibitor of transporters for organic cations. An open-label, 2-period, crossover, nonrandomized clinical trial was conducted in patients with neuropathic pain to evaluate the effect of CTZ on GBP pharmacokinetics. Twelve participants were treated with a single dose of 300 mg GBP (treatment A) or with 20 mg/d of CTZ for 5 days and 300 mg GBP on the last day of CTZ treatment (treatment B). Blood sampling and pain intensity evaluation were performed up to 36 hours after GBP administration. The interaction of GBP and CTZ with transporters for organic cations was studied in human embryonic kidney (HEK) cells expressing the organic cation transporters (OCTs), multidrug and toxin extrusion proteins (MATEs), and OCTN1. CTZ treatment resulted in reduced area under the concentration-time curve and peak concentration compared with treatment A. In treatment B, the lower plasma concentrations of GBP resulted in reduced pain attenuation. GBP renal clearance was similar between treatments. GBP has low apparent affinity for OCT2 (concentration of an inhibitor where the response [or binding] is reduced by half [IC ] 237 µmol/L) and a high apparent affinity for hMATE1 (IC 1.1 nmol/L), hMATE2-K (IC 39 nmol/L), and hOCTN1 (IC 2.1 nmol/L) in HEK cells. At therapeutic concentrations, CTZ interacts with hMATE1 and OCTN1. In summary, CTZ reduced the systemic exposure to GBP and its effect on neuropathic pain attenuation. However, CTZ × GBP interaction is not mediated by the renal transporters.
加巴喷丁（GBP）是一种主要以原形经尿液排泄的有机阳离子，已有研究提示药物主动分泌也可能参与其肾排泄。本研究旨在评估 GBP 与西替利嗪（CTZ，一种有机阳离子转运体抑制剂）之间的药物相互作用。采用开放标签、2 周期、交叉、非随机临床试验，纳入神经病理性疼痛患者，评估 CTZ 对 GBP 药代动力学的影响。12 例患者接受单次 300 mg GBP 治疗（A 组）或连续 5 天给予 20 mg/d CTZ 治疗后第 5 天给予 GBP 300 mg（B 组）。在 GBP 给药后 36 小时内进行血样采集和疼痛强度评估。采用表达有机阳离子转运体（OCTs）、多药和毒素外排蛋白（MATEs）和 OCTN1 的人胚肾（HEK）细胞研究 GBP 和 CTZ 与有机阳离子转运体的相互作用。与 A 组相比，CTZ 治疗使 GBP 的 AUC 0-t 和 C max 降低。B 组中 GBP 较低的血浆浓度导致疼痛缓解降低。两种治疗方案的 GBP 肾清除率相似。GBP 对 OCT2 的表观亲和力较低（使反应[或结合]降低一半的抑制剂浓度[IC 50 ]为 237 μmol/L），对 hMATE1（IC 1.1 nmol/L）、hMATE2-K（IC 39 nmol/L）和 hOCTN1（IC 2.1 nmol/L）的表观亲和力较高。在治疗浓度下，CTZ 与 hMATE1 和 hOCTN1 相互作用。总之，CTZ 降低了 GBP 的全身暴露量及其对神经病理性疼痛缓解的作用。然而，CTZ 与 GBP 的相互作用并非由肾转运体介导。
