Interaction of zotepine and chlorprothixene with URAT1-mediated urate transport

Zotepine and chlorprothixene are antipsychotic drugs, and they have a broad therapeutic effect in patients with schizophrenia. Zotepine and chlorprothixene have been reported to decrease serum urate levels. In addition, an increase in renal clearance of urate was shown in several studies. However, the molecular mechanism underlying these effects has not yet been clarified. In the present study, we measured [14C]urate uptake using stable cells expressing human urate transporter 1 (HEK-hURAT1) and mock cells (HEK-mock) to evaluate the uricosuric actions of zotepine and chlorprothixene. Zotepine and chlorprothixene inhibited URAT1-mediated [14C]urate uptake in a concentration-dependent manner (IC50 values were 14.52μM for zotepine and 6.08μM for chlorprothixene). Next, we measured the activity of xanthine oxidase (XO) to determine whether zotepine and chlorprothixene have inhibitory effects on urate production. Urate production mediated by XO was not inhibited. Taken together, the results suggest that URAT1, a major contributor of renal urate reabsorption and a major target of uricosuric drugs such as losartan and benzbromarone, interacted with zotepine and chlorprothixene; however, XO, a major enzyme in urate production, did not interact with zotepine or chlorprothixene. This is the first study showing that drugs that have the structure of a tricyclic compound interact with URAT1. Elucidation of these interactions may contribute to the development of new anti-hyperuricemic agents by clarifying the structure of the substrate-binding site of URAT1.