Serum uric acid (SUA) is currently recognized as a risk factor for cardiovascular disease. It has been reported that an angiotensin II receptor blocker (ARB), losartan, decreases SUA level, whereas other ARBs, such as candesartan, have no lowering effect. Because the renal uric acid transporter (URAT1) is an important factor controlling the SUA level, we examined the involvement of URAT1 in those differential effects of various ARBs on SUA level at clinically relevant concentrations. This study was done by using URAT1-expressing Xenopus oocytes. Losartan, pratosartan, and telmisartan exhibited cis-inhibitory effects on the uptake of uric acid by URAT1, whereas at higher concentrations, only telmisartan did, and these ARBs reduced the uptake in competitive inhibition kinetics. On the other hand,(a major metabolite of losartan), olmesartan, and valsartan were not inhibitory. Preloading of those ARBs in the oocytes enhanced the URAT1-mediated uric acid uptake, showing a trans-stimulatory effect. The present study is a first demonstration of the differential effects of ARBs on URAT1 that some ARBs are both cis-inhibitory and trans-stimulatory, depending on concentration, whereas others exhibit either a trans-stimulatory or cisinhibitory effect alone, which could explain the clinically observed differential effects of ARBs on SUA level. Furthermore, it was found that such differential effects of ARBs on URAT1 could be predicted from the partial chemical structures of ARBs, which will be useful information for the appropriate use and development of ARBs without an increase of SUA.Many observations indicate that hyperuricemia is associated with hypertension. Raised serum uric acid (SUA) levels are found in approximately 25% of hypertensive patients (Cannon et al., 1966;Messerli et al., 1980), and hypertension is present in 30% of patients with hyperuricemia or gout (Yu and Berger, 1982;Lin et al., 2000). Mazzali et al. (2001) showed that mild hyperuricemia was induced in rats given the uricase inhibitor oxonic acid, and the hyperuricemic rats developed elevated blood pressure, whereas control rats remained normotensive. Moreover, the development of hypertension was prevented by concurrent treatment with either a xanthine oxidase inhibitor (allopurinol) or a uricosuric agent (benzbromarone), both of which lowered the uric acid level (Mazzali et al., 2001). Therefore, these observations indicate that an increase of SUA level should be prevented, especially in patients with hypertension.It was reported that the angiotensin II receptor blocker (ARB) losartan (Fig.

Valsartan, olmesartan, and pratosartan could inhibit the OAT3-mediated uric acid secretion in clinical situations. Furthermore losartan could inhibit ATP-dependent uric acid secretion by MRP4. These effects may explain partially the alteration of serum uric acid level by ARBs.

The physiological function of organic anion transporter OAT2 (SLC22A7) remains unclear, but since OAT2 transports purine derivatives, it may be involved in renal handling of uric acid, the final metabolite of purine derivatives. In the present study, we studied uric acid transport in stably OAT2-expressing HEK293 cells (HEK293/OAT2). OAT2 mediated uptake, but not efflux, of [ ]uric acid uptake was inhibited by several mono-or dicarboxylic acids, but it was not trans-stimulated by any of the compounds tested. The pattern of inhibition of OAT2-mediated uric acid transport by various drugs was different from that of OAT1-or OAT3-mediated transport. Furthermore, OAT2-mediated transport of uric acid was inhibited by an antiuricosuric drug, pyrazinecarboxylic acid. These results revealed distinct characteristics of uric acid transport via OAT2 compared with other uric acid transporters, suggesting that OAT2 plays a role in renal uric acid uptake from blood as a first step of tubular secretion. OAT2 may therefore be a potential target for regulating serum uric acid level.

In Japan in October 2016, the Pharmaceuticals and Medical Devices Agency (PMDA) began to receive electronic data in new drug applications (NDAs). These electronic data are useful to conduct regulatory assessment of sponsors’ submissions and contribute to the PMDA's research. In this article, we summarize the number of submissions of quantitative modeling and simulation (M&S) documents in NDAs in Japan, and we describe our current thinking and activities about quantitative M&S in PMDA.

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