Interaction of buspirone and its major metabolites with human organic cation transporters

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 [³ H]-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 IC₅₀ of 26.3 ± 2.9 μM without any cytotoxic effects in HepG2 expressing hOCTs cells. Consistently, buspirone strongly inhibited [³ H]-MPP⁺ uptake by S2hOCT1, S2hOCT2, and S2hOCT3 cells with an IC_50s of 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 [³ H]-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.