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METABOLISM, TRANSPORT, AND PHARMACOGENOMICS
Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba, Japan (T.I., M.S., T.M., I.T.); and Department of Geriatric Medicine, Osaka University Graduate School of Medicine, Osaka, Japan (T.O.)
Received August 19, 2006; accepted October 12, 2006.
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Abstract |
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; 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. 1) increased excretion of uric acid and decreased the SUA level in both healthy and hypertensive subjects (Nakashima et al., 1992; Burnier et al., 1993; Fauvel et al., 1996), whereas the ARBs candesartan and valsartan did not affect the SUA level (Gonzalez-Ortiz et al., 2000; Malmqvist et al., 2000; Elliott et al., 2001). In a study of 1161 hypertensive patients, candesartan slightly but significantly increased the SUA level (Manolis et al., 2000). Thus, the effects of various ARBs on the disposition of uric acid might be different.
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). Urinary excretion of uric acid accounts for approximately 70% of the daily production of uric acid. The so-called "four-component hypothesis," including glomerular filtration, presecretory reabsorption, secretion, and postsecretory reabsorption, has been proposed to explain the renal handling of uric acid (Sica and Schoolwerth, 2000). It was reported that the uricosuric effect of losartan results from its inhibitory action on the urate/anion exchanger at the brush-border membranes of the renal proximal tubular epithelial cells (Roch-Ramel et al., 1997; Enomoto et al., 2002). Enomoto et al. (2002) found that the uric acid transporter URAT1 is involved in the reabsorption of uric acid from lumen to cytosol along the proximal tubule. In addition, they showed that the uric acid transport via URAT1 was inhibited by uricosuric benzbromarone and that the uptake of uric acid was trans-stimulated by antiuricosuric pyrazinecarboxylic acid (PZA), which is an active metabolite of pyrazinamide (Enomoto et al., 2002). Furthermore, mutation of URAT1 is associated with idiopathic renal hypouricemia (Ichida et al., 2004; Enomoto et al., 2002). These results indicated that URAT1 plays a dominant role in uric acid reabsorption in renal tubular epithelial cells. Roch-Ramel et al. (1997) reported that the uptake of uric acid by renal brush-border membrane vesicles was inhibited by losartan with an IC50 of 13 µM. Moreover, losartan at 1 mM completely blocked the uptake of uric acid via URAT1 (Enomoto et al., 2002). However, the maximal plasma total concentration of losartan was 0.65 µM after oral administration at the clinical dose of 50 mg in humans (Tamimi et al., 2005). Because plasma protein binding of losartan is 98.7% (Burnier, 2001), the maximal concentration of losartan in glomerularly filtered urine could be approximately 10 nM or less, assuming that the plasma-free concentration is equal to the concentration in the glomerular filtrate. These observations indicate that the previously reported inhibitory actions of ARBs on URAT1-mediated uric acid transport may not be clinically relevant.
Therefore, in the present study, to clarify the mechanism of the variable of the effects of ARBs on SUA level, we examined the cis-inhibitory and trans-stimulatory effects of ARBs at more clinically relevant concentrations focusing on URAT1. Recently, Price et al. (2006) showed that human vascular smooth muscle cells expressed URAT1 and examined the inhibitory effect of probenecid on uric acid uptake by the cells, suggesting that such mammalian tissue-derived cells would be useful for evaluation of transporters. However, to highlight URAT1 activity alone, heterologously URAT1-expressed cells are more useful than original tissue-derived cells. Accordingly, we used Xenopus oocytes expressed with URAT1 as the heterologous transporter expression system. This system is useful for the study of trans-stimulatory effect of ARBs on exchange transporter URAT1, which is one of the major purposes of the present study, because Xenopus oocyte can be directly preloaded with those test drugs into the cells by microinjection.
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Materials and Methods |
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), candesartan, and olmesartan were synthesized and kindly supplied by Kotobuki Pharmaceutical (Nagano, Japan). Benzbromarone and PZA were purchased from Sigma-Aldrich (St. Louis, MO) and Wako Pure Chemical Industries (Osaka, Japan), respectively. All other reagents were purchased from Sigma-Aldrich and Wako Pure Chemical Industries.
Uptake Experiments. Xenopus were purchased from Hamamatsu Biological Research Service, Inc. (Hamamatsu, Japan) and handled humanely according to the guidelines of the animal experimentation of Tokyo University of Science. Methods for preparation of oocytes, in vitro synthesis of URAT1 (SLC22A12)-cRNA, and standard uptake experiments were described previously (Iwanaga et al., 2005). In brief, the oocytes were injected with cRNA and cultured for 2 days and then preincubated in ND96 buffer (96 mM NaCl, 2 mM KCl, 1 mM MgCl2, 1.8 mM CaCl2, and 5 mM HEPES, pH 7.4) at 25°C for 15 min. To initiate uptake of [14C]uric acid, the oocytes were incubated with uptake buffer (96 mM sodium gluconate, 2 mM potassium gluconate, 1 mM magnesium gluconate, 1.8 mM calcium gluconate, and 5 mM HEPES, pH 7.4) containing 20 µM[14C]uric acid at 25°C for the designated time. In cis-inhibitory studies, tested drugs were added simultaneously with [14C]uric acid. In the trans-stimulation study, the oocytes were microinjected with 50 nl of drug solution or water containing 0.1% dimethyl sulfoxide (DMSO). Immediately after the microinjection (within approximately 2 min), the oocytes were transferred to uptake buffer containing [14C]uric acid to initiate uptake. In the cases of uptake study preloaded with PZA, cis-inhibitory effect was examined after preloading of the oocytes with PZA (50 nl of 100 mM PZA solution, pH 7.4) because PZA exhibits a strong trans-stimulatory effect on uric acid uptake, thereby eliminating almost completely the trans-stimulatory effect of ARBs added to the extracellular medium. Then, uptake of [14C]uric acid was measured in the same way as described above using uptake buffer containing 20 µM[14C]uric acid with or without test ARBs within 2 min. Uptake was terminated by washing the oocytes three times with ice-cold uptake buffer. The oocytes were solubilized with 5% sodium dodecyl sulfate solution. Radioactivity was measured using a liquid scintillation counter (Perkin Elmer, Boston, MA). Artifactual cis-inhibitory and trans-stimulatory effects were checked by using 1 µM benzbromarone and 100 mM PZA, respectively, in each assay because they have been well established as a strong inhibitor and a trans-stimulant of URAT1, respectively.
Uptake was expressed as the cell/medium ratio (microliters per oocyte), obtained by dividing the uptake amount by the concentration of substrate in the uptake buffer. In this study, we repeated each experiment more than two times to confirm the results, and the typical results were shown as mean and S.E.M. value obtained from 10 oocytes. To estimate the kinetic parameters for the uptake by URAT1, the initial uptake rates by URAT1 (obtained after subtraction of the uptake by water-injected oocytes from that by URAT1-cRNA injected oocytes) were fitted to the following eq. 1 by means of nonlinear least-squares regression analysis using the MULTI program (Yamaoka et al., 1981):
 | (1) |
 | (2) |
Estimation Volume of Oocytes. To evaluate the apparent intracellular volume of Xenopus laevis oocytes, antipyrine was used because it has a high membrane permeability and negligible protein binding (Terasaki et al., 1992). A 50-nl aliquot of 100 mM antipyrine was injected into oocytes that had been injected with URAT1-cRNA or water in advance, and then the oocytes were transferred to 0.5 ml of uptake buffer within 2 min to initiate the efflux of antipyrine. Antipyrine concentration in uptake buffer, arising by efflux from the oocyte, was measured by high-performance liquid chromatography with Alliance 2690 and UV486 instruments detected at 245 nm (Waters Co., Milford, MA). The analysis was performed on a Mightysil C18 column (4.6 x 150 mm; 5 µm; Kanto Chemical, Tokyo, Japan) at a flow rate of 1 ml/min, using a mobile phase consisting of a mixture of 10 mM sodium phosphate buffer, pH 7.0, and acetonitrile (80:20). The apparent volume of oocytes (microliters) was obtained by dividing the amount of antipyrine in one oocyte (picomoles) by the antipyrine concentration in uptake buffer (picomoles per microliter) at the steady state, on the assumption that the intracellular unbound concentration is equal to the concentration in uptake buffer at the steady state.
Statistical Analysis. Statistical significance was determined with Student's t test or by analysis of variance followed by Dunnett's test, and a p value of less than 0.05 was considered statistically significant.
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Results |
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), to estimate the URAT1-mediated transport of URAT1 clearly. In separate experiments, we confirmed that similar reductions of uric acid uptake were observed at the [14C]uric acid concentrations of 250 and 500 µM, which correspond to physiological concentrations of uric acid in serum in the presence of losartan or pratosartan, but not candesartan, at 10 nM (data not shown).
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Trans-Stimulatory Effects of ARBs on URAT1-Mediated Uric Acid Uptake. Trans-stimulatory effect of ARBs on uric acid uptake via URAT1 was examined by measuring the uptake of uric acid by oocytes preloaded with pratosartan. Uptake of [14C]uric acid by URAT1-expressing oocytes that were preloaded with pratosartan (0.1 pmol, 2 µM x 50 nl) at 15 min was significantly greater than that by oocytes preloaded with the same volume of water (see Supplemental Data I). Figure 3 shows the concentration dependence of trans-stimulatory effect of ARBs on the uptake of uric acid via URAT1. Immediately after the microinjection of ARB solution into oocytes, the uptake of [14C]uric acid was measured for 15 min. The results are shown as the uptake relative to that without ARB preloading. The tested ARBs increased the uptake of uric acid when preloaded at concentrations higher than 5 µM, except for EXP3174 (10 µM). The increment of [14C]uric acid uptake in the presence of pratosartan and losartan disappeared at injected concentrations higher than 50 µM, whereas the uptake was significantly increased by preloaded candesartan and EXP3174 at injected concentrations higher than 5 or 10 µM, respectively. Figure 4 compares the trans-stimulatory effect of ARBs on the uptake of uric acid by oocytes expressed with URAT1. Each oocyte was preloaded with 50 nl of 10 µM ARB solution, and the uptake of [14C]uric acid was evaluated for 15 min. Candesartan, EXP3174, losartan, olmesartan, pratosartan, and valsartan enhanced the uptake of uric acid, whereas telmisartan and benzbromarone showed no effect. Candesartan showed the highest enhancement of uptake.
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Estimation of Intracellular ARB Concentration after Preloading of Xenopus Oocytes. To estimate the concentration of ARBs in oocytes after microinjection, the intracellular volume of oocytes was estimated from the distribution volume of antipyrine. The efflux of antipyrine from oocytes was evaluated in terms of the amount of antipyrine in the extracellular incubation medium. By 150 min after antipyrine was injected, the efflux of antipyrine had attained a steady state, and the concentrations of antipyrine in the incubation medium (500 µl) were 81.2 and 80.3 µM for water-injected oocytes and for URAT1-cRNA-injected oocytes, respectively. Residual antipyrine in an oocyte amounted to 68.3 and 64.9 pmol, respectively. If antipyrine has a negligible intracellular binding and the intracellular free concentration of antipyrine is equal to that in the extracellular incubation medium, the intracellular volumes of the oocytes can be estimated to be 0.841 ± 0.067 and 0.808 ± 0.073 µl/oocyte, respectively; no significant difference was observed. Furthermore, we estimated the recovery ratio of antipyrine after microinjection (approximately 70%). Based on this result, it is possible to estimate the concentrations in oocytes after microinjection of drugs; when the injected amount was 0.5 pmol (10 µM x 50 nl), the ARB concentration in the oocyte was approximately 430 nM.
cis-Inhibitory Effects of ARBs on URAT1-Mediated Uric Acid Uptake Preloaded with PZA. The complicated effects of ARBs on uric acid transport shown in Fig. 2 may be explained by the occurrence of a cis-inhibitory effect at low concentrations and a trans-stimulatory effect at higher concentrations. Because PZA exhibits a strong trans-stimulatory effect on URAT1 (Enomoto et al., 2002), preloading of PZA should eliminate the apparent trans-stimulatory effect of ARBs and make the evaluation of cis-inhibitory effect of ARBs clearer. Accordingly, the cis-inhibitory effects of ARBs were examined in oocytes preloaded with PZA. Microinjection of 5 nmol (100 mM x 50 nl) of PZA resulted in higher uptakes of uric acid by oocytes compared with oocytes without preloading of PZA or with preloading of 0.5 pmol (10 µM x 50 nl) of pratosartan (see Supplemental Data II). As shown in Fig. 5, the uptake of uric acid at 30 min was reduced by 10 nM pratosartan and losartan to be less than half, showing clearer effects than those in Fig. 2. Telmisartan and benzbromarone also reduced the uptake, whereas the other ARBs did not cause a significant reduction. Furthermore, the inhibition kinetics of losartan, pratosartan, and telmisartan were analyzed and are shown by Eadie-Hofstee plots in Fig. 6, A to C. All three ARBs increased Km from 357.6 ± 8.2 to 822.1 ± 146.7, 895.1 ± 101.3, and 554.0 ± 35.5 µM, respectively, but did not change Vmax (from 750.0 ± 8.3 to 783.2 ± 54.9, 775.2 ± 44.7, and 736.6 ± 23.9 pmol/30 min/oocyte, respectively). Accordingly, these ARBs were shown to inhibit URAT1 in a competitive manner, and their Ki values were 7.7, 6.7, and 18.2 nM, respectively. In addition, to clarify the mechanism of trans-stimulatory effect of PZA, kinetic parameters of URAT1-mediated uric acid uptake were compared with or without microinjection of PZA. As a result, microinjection of PZA increased Vmax from 73.1 ± 2.6 to 750.0 ± 8.3 pmol/30 min/oocyte uric acid uptake via URAT1, whereas only little change in Km value was observed (288.2 ± 16.9 to 357.6 ± 8.2 µM) (Fig. 6D).
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Discussion |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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). An elevation of 1 mg/dl SUA level has been suggested to be comparable to an elevation of 10 mm Hg systolic blood pressure (Alderman et al., 1999). Several ARBs have been reported to increase the SUA level, whereas losartan decreases it (Nakashima et al., 1992; Burnier et al., 1993; Fauvel et al., 1996; Manolis et al., 2000). Accordingly, it is important to clarify the mechanism of the changes of the SUA level by ARBs. SUA level is mainly controlled by the production of uric acid in liver, for which the rate-limiting enzyme is xanthine oxidase, and by renal handling, such as reabsorption by the uric acid transporter URAT1 and secretion via other transporters. Among these factors that affect SUA level, the effects of ARBs on URAT1 were examined in the present study because URAT1 predominantly contributes to the renal reabsorption of uric acid across the apical membrane of proximal tubular epithelial cells (Enomoto et al., 2002), and previous studies suggested that renal uric acid transporter is involved as the mechanism for the effect of ARBs on SUA level (Roch-Ramel et al., 1997; Enomoto et al., 2002). Furthermore, because URAT1 is an anion/uric acid exchanger, and compounds such as PZA and lactic acid stimulate the reabsorption of uric acid, modulation of URAT1 may explain both the reduction and increment of SUA level by cis-inhibition and trans-stimulation of URAT1, respectively, by ARBs. However, no studies on the mechanism of differential effects of various ARBs on the SUA level via URAT1 have been reported. Accordingly, in the present study, we examined the cis-inhibitory and trans-stimulatory effects of ARBs on the uptake of uric acid via URAT1 at clinically relevant concentrations.
First of all, losartan and pratosartan exhibited inhibitory effects on the uptake of uric acid by URAT1 in the clinically relevant concentration range (0.1 to 10 nM), whereas others, such as candesartan and EXP3174, did not. These results suggested that losartan and pratosartan are potent inhibitors of URAT1, which would explain the decrease of the SUA level by these compounds in the clinic. The lack of inhibitory effect of candesartan, valsartan, and EXP3174 on URAT1 may be the reason why these ARBs do not decrease the SUA level. An interesting observation was the recovery of the uptake of [14C]uric acid at higher concentrations of losartan and pratosartan, as shown in Fig. 2. Because the recovery might be explained by a trans-stimulation of those ARBs at higher concentrations, their trans-stimulatory effects were examined, as shown in Figs. 3 and 4. With the exception of telmisartan, all of the ARBs preloaded into oocytes enhanced the uptake of [14C]uric acid. These results demonstrated that some ARBs exhibit both cis-inhibitory and trans-stimulatory effects on URAT1-mediated uptake of uric acid, depending on the concentration, whereas other ARBs have only a transstimulatory or a cis-inhibitory effect. Such differences in the effects on URAT1 among ARBs may explain the differential clinical observation of ARBs on SUA levels.
Quantitative estimation of the inhibitory action of ARBs on URAT1 is important to assess the clinical relevance. However, because of the dual effects of ARBs on URAT1, as shown in Fig. 2, the apparent cis-inhibitory effect might be underestimated. Therefore, we evaluated the actual cis-inhibitory effect of these ARBs on URAT1-mediated uric acid uptake by using PZA as a trans-stimulant of the uptake of [14C]uric acid via URAT1. Because PZA preloaded in the oocytes exhibited a stronger trans-stimulatory effect on uric acid uptake than ARBs (see Supplemental Data II), the apparent trans-stimulatory effect of ARBs observed in experiments such as those in Fig. 2 should be negligible in the presence of preloaded PZA. Furthermore, since no change was observed in Km (Fig. 6D), the increment of URAT1-mediated uptake of uric acid by PZA is due to the increase of Vmax, and characteristics of binding site of uric acid and inhibitors on URAT1 should be maintained. Therefor, PZA can be used for further studies about the effect of ARBs on URAT1. As shown in Fig. 5, the cis-inhibitory effects of losartan, pratosartan, and telmisartan in PZA-preloaded oocytes were stronger than the effects shown in Fig. 2, whereas other ARBs did not show any effect.
The maximal plasma concentrations of losartan and pratosartan are approximately 600 (Tamimi et al., 2005) and 2330 (A. Erihara, unpublished data) nM, respectively, and their plasma protein bindings are 98.7% (Burnier, 2001) and 98.0% (M. Sato, unpublished data), respectively. Accordingly, their concentrations in glomerularly filtered urine are estimated to be 8 and 47 nM, which are higher than their observed Ki values, 7.7 and 6.7 nM for losartan and pratosartan, respectively, suggesting that they could exhibit cis-inhibitory effect on uric acid transport via URAT1 in the clinical situation. However, they are also trans-stimulatory as shown in Fig. 3. We roughly estimated the intracellular concentrations of preloaded ARBs in oocytes by measuring the effective intracellular volume of the oocytes based on the distribution volume of antipyrine (0.841 and 0.808 µl/oocyte for water-injected and URAT1-cRNA-injected oocytes, respectively). The estimated ARB concentration in oocyte was approximately 430 nM after the microinjection of 10 µM solution. Because the tissue/plasma concentration ratios (Kp value) of losartan and pratosartan are 1.44 and 1.27 in kidney (S. Hanawa, unpublished data), their concentrations in renal tubular epithelial cells could be approximately 860 and 3000 nM, respectively. At these concentrations, trans-stimulatory effects could be possible. However, in the case of pratosartan, trans-stimulatory effect was disappeared when microinjected concentration was increased up to 100 µM (estimated intracellular concentration of oocyte was 4.3 µM) and at this condition, observed extracellular pratosartan that was effluxed from the oocytes was 8 nM in this study. Therefore, although pratosartan exhibits trans-stimulatory effect at clinical dose, it is considered that cis-inhibitory effect is more potent. Similar explanation can be applicable for losartan.
Candesartan, EXP3174, olmesartan, and valsartan did not exhibit a cis-inhibitory effect (Fig. 5) but showed a trans-stimulatory effect (Fig. 4). Such trans-stimulatory effects may lead to an increase of SUA level. The maximal plasma concentration of candesartan is 125 nM after oral administration of the clinical dose of 4 mg in humans (Suzuki and Yano, 1996). Because the Kp value of candesartan is approximately 0.6 in kidney (Kondo et al., 1996), the candesartan concentration in renal tubular epithelial cells could be 80 nM. Because this concentration is close to the estimate at which candesartan caused a trans-stimulatory effect, trans-stimulation of URAT1 by candesartan may at least partly explain the elevation of SUA level, whereas the contribution of other mechanisms cannot be excluded. Other ARBs that we examined, such as olmesartan and valsartan, might cause a trans-stimulatory effect through this mechanism, because their concentrations in renal tubular epithelial cells were estimated to be 1400 and 3900 nM, respectively, assuming the same Kp values as for candesartan (Schwocho and Masonson, 2001; Kimura et al., 2002).
It is interesting that telmisartan exhibited only a cis-inhibitory effect but not a trans-stimulatory effect. Although the inhibitory effect of telmisartan on URAT1 was potent, the urinary excretion of telmisartan is less than 0.02% of the dose, which is less than that of losartan (3.7%), candesartan (11%), or valsartan (11.5%). Accordingly, a uricosuric effect of telmisartan might not be observed clinically. To our knowledge, there is no clinical report concerning the effect of telmisartan on SUA level.
The present observation provided an idea of structure-activity relationship on the point of cis-inhibitory and trans-stimulatory effects of ARBs, namely, anionic moieties in carboxyl and tetrazolyl groups important to determine the differential effects among ARBs (Fig. 1). Losartan, pratosartan, and telmisartan that have one anionic moiety exhibited stronger cis-inhibitory effects than trans-stimulatory effects. Others, candesartan, olmesartan, and valsartan, with two anionic moieties did not show cis-inhibitory effects but showed trans-stimulatory effects. Furthermore, telmisartan that has no tetrazolyl moiety was not trans-stimulatory. Therefore, prediction of the effects of ARBs on URAT1 activity may be possible by focusing on the acidic moieties of them.
In conclusion, although several mechanisms may be involved in the variable effects of ARBs on SUA levels, in the present study, we found that different ARBs seem to have different effects (cis-inhibition, trans-stimulation, or both) on uric acid transport via URAT1, depending on their concentrations. Some of those ARB effects should occur at the clinically relevant concentration range. To fully understand the interaction between uric acid and ARBs, we further need to examine the possible effects of these drugs on uric acid-related enzymes and other transporters.
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Footnotes |
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ABBREVIATIONS: SUA, serum uric acid; ARB, angiotensin II receptor blocker; URAT1, uric acid transporter; PZA, pyrazinecarboxylic acid; DMSO, dimethyl sulfoxide; EXP3174, (2-n-butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-5-carboxylic acid.
The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material. 
Address correspondence to: Dr. Ikumi Tamai, Department of Molecular Biopharmaceutics, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamasaki, Noda, Chiba 278-8510, Japan. E-mail: tamai{at}rs.noda.tus.ac.jp
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