Hyperuricemia is common in chronic kidney disease (CKD). Hyperuricemia is not only a result of CKD but may also be a cause of incidence and progression of CKD. This scenario composes a chicken and egg problem, which should be resolved by an interventional randomized controlled trial. Until accumulating evidence is available, consensus on the treatment of asymptomatic hyperuricemia in CKD remains to be established. The treatment is first done with nutritional instruction and life-style modification such as reducing alcohol consumption. If insufficient, uric acid lowering drugs will be administered; xanthine oxidase inhibitor or uricosuric agent. In some situation both drugs can be given simultaneously according to the disease type of hyperuricemia which can be simply examined by spot urine. Target range of serum uric acid has not been determined yet but we recommend to be less than 6.5 mg/dL for present in order to inhibit the progression of CKD reaching to end-stage renal disease. Ongoing randomized controlled trials may open a new era of the hyperuricemia in CKD. ABCG2 in the intestine may play a compensatory role in face of decreasing uric acid excretion to urine. The mechanism of the upregulation of ABCG2 in CKD and signal transduction in the cell should be further investigated.
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.