Interaction of buspirone and its major metabolites with human organic cation transporters
Interaction of buspirone and its major metabolites with human organic cation transporters
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丁螺环酮及其主要代谢物与人体有机阳离子转运蛋白的相互作用
DOI：
10.1111/fcp.12883
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发表时间：
2023
影响因子：
2.9
通讯作者：
Vaddhanaphuti Chutima S.
中科院分区：
文献类型：
--
作者：
Jinakote Metee;Jutabha Promsuk;Anzai Naohiko;Ontawong Atcharaporn;Soodvilai Sunhapas;Inchai Jakkapong;Vaddhanaphuti Chutima S.
丁螺环酮是一种阳离子药物，是一种抗焦虑和抗抑郁药物。然而，丁螺环酮及其代谢产物是否与有机阳离子转运蛋白相互作用仍不确定。在本研究中，我们使用人肝细胞癌（HepG 2）、人结直肠腺癌（Caco-2）细胞和表达OCT 1（S2 hOCT 1）、2（S2 hOCT 2）或3（S2 hOCT 3）的S2细胞，检查了丁螺环酮及其主要代谢产物1-（2-嘧啶基）哌嗪（1-PP）和6-羟基丁螺环酮（6′-OH-Bu）与hOCT的相互作用。使用HepG 2细胞检查丁螺环酮和荧光4-（4-（二甲基氨基）苯乙烯基）-N-甲基吡啶鎓（ASP+）的联合给药，并在过表达hOCT的S2细胞中评估[3 H]-1-甲基-4-苯基吡啶鎓（MPP+）转运。结果表明，丁螺环酮可抑制ASP+转运，IC 50为26.3 ± 2.9 μM，对表达HepG 2的hOCT细胞无任何细胞毒性作用。因此，丁螺环酮强烈抑制S2 hOCT 1、S2 hOCT 2和S2 hOCT 3细胞的[3 H]-MPP+摄取，IC 50分别为89.0 ± 1.3 μM、43.7 ± 7.5 μM和20.4 ± 1.0 μM。尽管如此，6′-OH-Bu和1-PP对ASP+和[3 H]-MPP+转运产生弱抑制或无抑制。这些发现表明丁螺环酮与由hOCT 3处理的有机阳离子药物的潜在相互作用。然而，需要进一步的临床相关性来支持这些研究结果，以预防与丁螺环酮一起服用处方药的患者中的药物相互作用。
Buspirone, a cationic drug, is an anxiolytic and antidepressant drug. However, whether buspirone and its metabolites are interacted with organic cationic transporter remains uncertain. In this study, we examined the interaction of buspirone and its major metabolites 1‐(2‐pyrimidinyl)piperazine (1‐PP) and 6‐hydroxybuspirone (6′‐OH‐Bu) with hOCTs using human hepatocellular carcinoma (HepG2), human colorectal adenocarcinoma (Caco‐2) cells, and S2 cells expressing OCT1 (S2hOCT1), 2 (S2hOCT2), or 3 (S2hOCT3). Coadministration of buspirone and fluorescent 4‐(4‐(dimethylamino)styryl)‐N‐methylpyridinium (ASP+) was examined using HepG2 cells, and [3H]‐1‐methyl‐4‐phenylpyridinium (MPP+) transport was assessed in S2 cell overexpressing hOCTs. The results showed that ASP+transport was suppressed by buspirone with an IC50of 26.3 ± 2.9 μM without any cytotoxic effects in HepG2 expressing hOCTs cells. Consistently, buspirone strongly inhibited [3H]‐MPP+uptake by S2hOCT1, S2hOCT2, and S2hOCT3 cells with an IC50sof 89.0 ± 1.3 μM, 43.7 ± 7.5 μM, and 20.4 ± 1.0 μM, respectively. Nonetheless, 6′‐OH‐Bu and 1‐PP caused weak or no inhibition on ASP+and [3H]‐MPP+transport. These findings suggest the potential interaction of buspirone with organic cation drugs that are handled by hOCT3. However, further clinical relevance is needed to support these findings for preventing drug–drug interaction in patients who take prescribed drugs together with buspirone.