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Salivary secretory carcinoma (SASC) is frequently associated with ETV6-neurotrophic tyrosine receptor kinase (NTRK) 3 fusion and more rarely with RET, MET, or ALK rearrangement. We aimed to elucidate the potential diagnostic utility of pan-tropomyosin receptor kinase (Trk) immunohistochemistry and its relationship with the fusion gene subtype in SASC. We examined 33 cases of SASC for immunoexpression of pan-Trk, ALK and ROS1, and gene rearrangement of the ETV6, NTRK3, and RET genes using fluorescence in situ hybridization (FISH) and reverse transcription-polymerase chain reaction (RT-PCR). Thirty (90.9%) of 33 SASCs harbored ETV6-NTRK3 fusion gene transcripts by RT-PCR and/or both ETV6 and NTRK3 gene rearrangements by FISH, and 3 cases (9.1%) had RET gene rearrangement. Most NTRK3-rearranged SASCs (27/33 cases; 81.8%) had conventional ETV6 exon 5-NTRK3 exon 15 fusion, whereas 2 cases (6.1%) had both the conventional fusion and a novel ETV6 exon 4-NTRK3 exon 15 fusion variant. In the remaining one case (3%), only FISH revealed both ETV6 and NTRK3 rearrangements, suggesting an ETV6-NTRK3 fusion with an as yet undetermined break point. All 30 SASCs with ETV6-NTRK3 fusion and/or NTRK3 rearrangement showed nuclear and cytoplasmic immunoreactivity for pan-Trk. In contrast, 3 SASCs with RET rearrangement showed negative or only weak cytoplasmic staining for pan-Trk. There was no case harboring ALK and ROS1 rearrangements. All 17 non-SASC tumors were negative for pan-Trk. The results suggest that nuclear and cytoplasmic immunoreactivity for pan-TRK may be helpful to identify ETV6-NTRK3-fused SASCs and to distinguish them from RET-rearranged SASCs and morphological mimics.

Summary NTRK1/3, ALK, and ROS1 translocations have been reported in a minor subset of papillary thyroid carcinomas (PTCs). We aimed to elucidate the prevalence and clinicopathological characteristics of these gene rearrangements and the utility of immunohistochemistry (IHC) in PTC and anaplastic thyroid carcinoma (ATC). We screened nonradiation-exposed cases of 307 PTCs and 16 ATCs by IHC for pan-Trk, ALK, and ROS1, followed by fluorescence in situ hybridization (FISH). In the PTC group, IHC for pan-Trk, ALK, and ROS1 was positive in 18 cases (5.9%), 1 case (0.3%), and 12 cases (3.9%), respectively. Among the pan-Trk IHC–positive cases (n = 18), 2 cases (11.1%; 0.7% of all PTCs) had NTRK1 or NTRK3 gene rearrangement with conventional PTC histology. The ALK IHC–positive case (n = 1) was the follicular variant of PTC with consistent ALK gene rearrangement. ROS1 gene rearrangement was not detectable in the ROS1 IHC–positive PTCs (0/12) by FISH. Most (approximately 70%) of the pan-Trk or ROS1 IHC–positive/FISH–negative cases had BRAF gene mutation with conventional PTC morphology. In the ATC group, neither ALK nor ROS1 IHC was positive, whereas pan-Trk IHC was positive in 1 case (6.3%) in which NTRK1 gene rearrangement was confirmed by FISH. These results suggest that NTRK, ALK, and ROS1 rearrangements are rare molecular events in nonradiation-exposed Japanese patients with PTC and ATC. Although IHC is not an entirely specific surrogate for these abnormalities and does not serve as a stand-alone companion diagnosis, the combined use of IHC and molecular testing may be helpful for determining promising therapeutic strategies with tyrosine kinase inhibitors.

Differential diagnosis among basal cell adenoma (BCA), basal cell adenocarcinoma (BCAC), adenoid cystic carcinoma (ACC) and pleomorphic adenoma (PA) of the salivary gland can be challenging due to their similar histological appearance. Although frequent nuclear β-catenin expression and CTNNB1 mutations have been reported in BCA, further details of the Wnt/β-catenin signal alterations are unclear. The aim of this study was to assess the diagnostic utility of Wnt/β-catenin signal alteration in BCA and morphological mimics. We performed immunohistochemical staining for β-catenin and mutation analysis for Wnt/β-catenin-related genes (CTNNB1, APC, AXIN1 and AXIN2) in BCA (n = 34), BCAC (n = 3), ACC (n = 67) and PA (n = 31). We also analyzed ACC-specific MYB and MYBL1 gene rearrangements by fluorescence in situ hybridization (FISH). Nuclear β-catenin expression (≥3%) was present in 32/34 cases (94.1%) of BCA, and the nuclear β-catenin labeling index was significantly higher than in other tumor types (p = 0.0001). In BCA, we found mutations in CTNNB1, APC and AXIN1 genes (41.1%, 2.9% and 8.8%, respectively). In BCAC, nuclear β-catenin expression with CTNNB1 mutation was present in 1/3 cases (33.3%). As for ACC, nuclear β-catenin expression was observed in 3/67 cases (4.4%), but all 3 cases harbored either MYB or MYBL1 gene rearrangement. The results suggest that nuclear β-catenin immunoreactivity with appropriate criteria may be helpful to distinguish BCA from histologically similar tumors. However, a minor subset of ACCs with nuclear β-catenin expression require careful diagnosis. In addition, Wnt/β-catenin signal alteration may play a role in the pathogenesis of BCA and BCAC.

Bosentan is a substrate of hepatic uptake transporter organic anion-transporting polypeptides (OATPs), and undergoes extensive hepatic metabolism by cytochrome P450 (P450), namely, CYP3A4 and CYP2C9. Several clinical investigations have reported a nonlinear relationship between bosentan doses and its systemic exposure, which likely involves the saturation of OATP-mediated uptake, P450-mediated metabolism, or both in the liver. Yet, the underlying causes for the nonlinear bosentan pharmacokinetics are not fully delineated. To address this, we performed physiologically based pharmacokinetic (PBPK) modeling analyses for bosentan after its intravenous administration at different doses. As a bottom-up approach, PBPK modeling analyses were performed using in vitro kinetic parameters, other relevant parameters, and scaling factors. As top-down approaches, three different types of PBPK models that incorporate the saturation of hepatic uptake, metabolism, or both were compared. The prediction from the bottom-up approach (models 1 and 2) yielded blood bosentan concentration-time profiles and their systemic clearance values that were not in good agreement with the clinically observed data. From top-down approaches (models 3, 4, 5-1, and 5-2), the prediction accuracy was best only with the incorporation of the saturable hepatic uptake for bosentan. Taken together, the PBPK models for bosentan were successfully established, and the comparison of different PBPK models identified the saturation of the hepatic uptake process as a major contributing factor for the nonlinear pharmacokinetics of bosentan.

Background Differentiating inverted papilloma from squamous cell carcinoma (SCC) is sometimes difficult. We evaluated the clinical usefulness of serum SCCA1 and SCCA2 in the management of patients with inverted papilloma or SCC. Methods Serum and tissue samples for the analysis of SCCA1, SCCA2, and SCC antigen were taken from 18 patients with sinonasal inverted papilloma and 23 cases with sinonasal SCC. The SCCA1, SCCA2, and SCC antigen levels were determined. Results The serum SCCA1 concentration was significantly higher in the inverted papilloma group than in the SCC group, whereas the serum SCCA2 level was significantly higher in the SCC group than in the inverted papilloma group. Conclusion Patients with sinonasal inverted papilloma predominantly express SCCA1 protein, whereas those with SCC predominantly express SCCA2. This suggests that combined measurements of both serum SCCA1 and SCCA2 concentrations can be very useful for distinguishing sinonasal inverted papilloma from SCC.

Six patients with acute Type A aortic dissection were medically treated due to advanced age, patient refusal and comorbidity despite surgical indication. Computed tomography after onset revealed a thrombosed false lumen in 3 patients and a patent false lumen with flap in 3 patients. All patients were stable during admission except 1 patient who presented with shock. After admission, treatment including strict control of systolic blood pressure was started according to a predetermined treatment strategy. All patients had no significant complications during hospitalization. All patients survived and returned to their usual activities. Medical treatment for stable elderly patients is a possible therapeutic option for acute Type A aortic dissection.

Distant metastasis of primary squamous cell carcinoma (SCC) of the thyroid gland is rare and, to the best of our knowledge, cardiac metastasis has not been reported to date. A 57-year-old man underwent surgery and adjuvant chemoradiotherapy for stage IVA SCC of the thyroid gland. After 3 months, the patient was admitted to the Kyushu University Hospital (Fukuoka, Japan) with subcutaneous hematomas of the left thigh and lower leg, and he was diagnosed with cardiac and mediastinal lymph node metastases of SCC of the thyroid gland with severe disseminated intravascular coagulation (DIC). Echocardiography revealed a mass, 52 mm in greatest diameter, protruding from the interventricular septum towards the right ventricle. Weekly administration of paclitaxel and concurrent irradiation of the cardiac and lymph node metastases were performed. Eighteen days after the initiation of chemoradiotherapy, the DIC and hematomas had significantly improved, and the cardiac metastasis was stable. However, 2 months after admission, the patient developed dyspnea and multiple nodular shadows appeared to be spreading in the subpleura of the lungs bilaterally, which were initially suspected to be pulmonary tumor embolisms. Prednisolone and subsequent administration of lenvatinib were not effective and the patient succumbed to respiratory failure. Severe DIC caused by extremely rare cardiac metastasis of SCC of the thyroid gland was effectively controlled by chemoradiotherapy. However, intensive local control appears to be required for this condition.

The requirement for data on the inhibition and involvement of transporters in the pharmacokinetics of drugs in regulatory applications has increased considerably over the last few decades as the knowledge around drug transporters has evolved and regulatory guidance documents have been regularly updated. Drug interactions guidance from the European Medicines Agency (EMA), US Food and Drug Administration (FDA) and Japanese Ministry of Health, Labour and Welfare (MHLW)/Pharmaceuticals and Medical Devices Agency (PMDA) gives detailed information on the data that are recommended in applications, including decision trees on the need to study specific transporters. This chapter will describe strategies to determine the potential for drug interactions and the exposure of the drug in all sub-populations with altered transport protein activity, and how such data should be presented in the drug labels. Alongside this, the process for submission of new drug applications to respective agencies is described, including processes for obtaining advice from the respective agencies with particular emphasis on transporter mediated interactions.

A 64-year-old woman was referred to our hospital with palpitation and exertional dyspnea. An electrocardiogram showed sinus rhythm, but supraventricular tachycardia was recorded on Holter monitoring. Multidetector computed tomography revealed a small left ventricular outpouching in the apex, with a narrow connection to the ventricle and normal coronary arteries. Surgery for the left ventricular pouch was performed successfully. Histological examination demonstrated that the left ventricular diverticulum consisted of three layers of the ventricular wall, with the myocardial layer mostly replaced by fibrous tissue. The patient has been well after surgery.

Objective The aim of this study was to investigate the clinical features and prognosis of patients with squamous cell carcinoma (SCC) associated with sinonasal inverted papilloma (IP). Methods The medical records of 95 patients who were diagnosed with IP or SCC associated with IP were retrospectively reviewed. Out of 95 patients, 15 were diagnosed with SCC associated with IP. The clinical characteristics, treatment modalities, and survival outcomes of the patients were analyzed. Results The incidence of SCC associated with IP was 15.8%. Although differential diagnosis between IP and SCC associated with IP is difficult, epistaxis may be the specific symptom in SCC associated with IP cases. The 3-year disease-specific survival rate was higher in cases with T1, 2 and 3 than in cases with T4. There was no significant difference in survival rate between maxillary sinus and other primary sites. On the other hand, there was a significant difference in survival rate between the microscopic SCC with IP cases and the other cases. In addition, the patients with 70 years old with a 3-year disease free survival of 80% versus 0%. Conclusions Some T4 patients were found to have a highly aggressive disease. Therefore, complete surgical resection followed by chemo-radiation therapy is the recommended treatment for patients with T4 disease to control of the primary tumor site.

Since in vitro cell culture models often show altered apical transporter expression, they are not necessarily suitable for the analysis of renal transport processes. Therefore, we aimed here to investigate the usefulness of primary-cultured rat proximal tubular cells (PTCs) for this purpose. After isolation of renal cortical cells from rat kidneys, PTCs were enriched and the gene expression and function of apical transporters were analyzed by means of microarray, RT-PCR and uptake experiments. RT-PCR confirmed that the major apical transporters were expressed in rat PTCs. Na(+)-dependent uptake of α-methyl-d-glucopyranoside (αMG), ergothioneine and carnitine by the PTCs suggests functional expression of Sglts, Octn1 and Octn2, respectively. Inhibition of pH-dependent glycylsarcosine uptake by low concentration of cephalexin, which is a β-lactam antibiotics recognized by Pepts, indicates a predominant role of high affinity type Pept2, but not low affinity type Pept1, in the PTCs. Moreover, the permeability ratio of [(14)C]αMG (apical to basolateral/basolateral to apical) across PTCs was 4.3, suggesting that Sglt-mediated reabsorptive transport is characterized. In conclusion, our results indicate that rat PTCs in primary culture are found to be a promising in vitro model to evaluate reabsorption processes mediated at least by Sglts, Pept2, Octn1 and Octn2.

L-Citrulline has diagnostic potential for renal function, because its plasma concentration increases with the progression of renal failure. Although L-citrulline extracted by glomerular filtration in kidney is mostly reabsorbed, the mechanism involved is not clearly understood. The present study was designed to characterize L-citrulline transport across the apical membranes of renal epithelial tubular cells, using primary-cultured rat renal proximal tubular cells, as well as the human kidney proximal tubular cell line HK-2. L-Citrulline was transported in a Na+-dependent manner from the apical side of both cell types cultured on permeable supports with a microporous membrane. Kinetic analysis indicated that the transport involves two distinct Na+-dependent saturable systems and one Na+-independent saturable system in HK-2 cells. The uptake was competitively inhibited by neutral and cationic, but not anionic amino acids. Relatively large cationic and anionic compounds inhibited the uptake, but smaller ones did not. In HK-2 cells, mRNA expression of SLC6A19 and SLC7A9, which encode B0AT1 and b0,+AT, respectively, was detected by RT-PCR. In addition, L-citrulline transport was significantly decreased in HK-2 cells in which either SLC6A19 or SLC7A9 was silenced. Hence, these results suggest that amino acid transporters B0AT1 and b0,+AT are involved in the reabsorption of L-citrulline in the kidney, at least in part, by mediating the apical membrane transport of L-citrulline in renal tubule cells. Copyright © 2009 John Wiley & Sons, Ltd.

A 37-year-old male was transferred to our hospital with a diagnosis of acute myocardial infarction and a mass in the ascending aorta. Echocardiography revealed dyskinesia on the left ventricular apex and a floating mass lesion just above the aortic valve. Acute myocardial infarction was considered to be caused by embolism from the floating mass in the ascending aorta. Emergency surgery was successfully performed and histological examination showed the extirpated mass in the ascending aorta was thrombus. The patient has been well on oral anticoagulant and no recurrence has been seen on echocardiogram 4 years after the operation.

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, candesartan, EXP3174 [2-n-butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yI)methyl]imidazole-5-carboxylic acid] (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 cis-inhibitory 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.

Objective: the objective of this study was to carry out histomorphometric analysis on the combination of rifamycin SV monosodium salt with synthetic hydroxyapatite for bone repair in rabbit tibiae. Material and Methods: twelve male white rabbits were equally divided into test group and control group. Drill hole defects were created in the tibia of the animals and were filled with either synthetic hydroxyapatite and physiological solution (control group) or with the combination of synthetic hydroxyapatite and rifamycin SV monosodium salt (test group). Moreover, all defects were covered by expanded polytetrafluoroethylene barriers. The animals were euthanized at 7, 14, or 21 days. The tissue sections were mounted onto slides (hematoxylin and eosin stains) and were analyzed using an optical microscope. Results: the tested association presented better microbiological local control, faster bone matrix deposition rate, and higher final total amount of bone matrix deposition. Conclusion: the combination of rifamycin with synthetic hydroxyapatite seems to be advantageous under the tested conditions, encouraging the development of new animal model studies.

This report documents the sudden onset of aortic regurgitation (AR) by an exceptional cause. A 68-year-old woman suddenly experienced general fatigue, and AR was diagnosed. One year later, we performed aortic valve replacement. At surgery, three aortic cusps with a larger noncoronary cusp had prolapsed along with a free-floating fibrous band that had previously anchored the cusp to the aortic wall. Its rupture had induced the sudden onset of AR. There was no sign of infectious endocarditis. We performed successful aortic valve replacement.

A-79-year-old woman underwent percutaneous coronary intervention (PCI) to the right coronary artery (RCA) for effort angina, followed by intravascular ultrasonography (IVUS) to ascertain stent expansion. The IVUS catheter became entangled in the stent and could not be withdrawn from the outside. The patient was transferred to our hospital for its surgical removal. For the emergent surgery, we opened the stent region in the RCA and directly removed the IVUS catheter with the twisted stent. Additional coronary artery bypass grafting (CABG) involving three vessels was performed. She was discharged 42 days after surgery.

A 73-year-old woman with a 10-year history of myelodysplastic syndrome (MDS) had severe aortic regurgitation (AR) and an ascending thoracic aortic aneurysm (TAA) with a maximum diameter of 55 mm. By retrograde cerebral perfusion (RCP) in the patient under deep hypothermic circulatory arrest (DHCA), we replaced the ascending aorta graft and aortic valve. After surgery, we periodically administered granulocyte colony-stimulating factor (GCSF) with platelet aggregation. On postoperative day 20, the patient had a duodenal ulcer. On postoperative day 22, she had a subarachnoid hemorrhage, which was treated, nonoperatively, with a hemostatic agent. On postoperative day 126, she was discharged without sequelae, and 1.5 years after the surgery, she has had neither heart failure nor deterioration of MDS.

Elevated serum uric acid level has been associated with increased cardiovascular risk in hypertensive patients. Several angiotensin II receptor blockers exhibit differential effects on regulation of serum uric acid level in humans. We have demonstrated that some angiotensin II receptor blockers trans-stimulate the uptake of uric acid by human URAT1 and others inhibit the transport of uric acid mediated by human URAT1, OAT1, OAT3 and MRP4 in vitro. This study investigated the effects of candesartan, pratosartan and telmisartan on renal handling of uric acid in rats in vivo and in vitro. Candesartan (0.1 mg/kg) significantly decreased the urinary excretion of uric acid and increased the plasma uric acid concentration. The kidney candesartan level after low-dose treatment is close to that required to trans-stimulate uric acid uptake in vitro. Pratosartan exhibited dose-dependent hypouricemic and uricosuric effects, while telmisartan showed no effects on plasma uric acid level. Furthermore, we confirmed the effects of the tested drugs on uric acid transport by rat renal brush border membrane transporter(s) and basolateral Oat1 and Oat3. Effects of angiotensin II receptor blockers in rats may be mainly determined by their intrinsic effects (cis-inhibition and trans-stimulation) on uric acid reabsorption transporter(s) and their pharmacokinetic properties in rats.

Grossmann法はPBIの時間的変動を觀察する目的に適したPBI測定法である. これをさらに檢討改良した. 本法を用いて各種疾患の有熱群ならびに無熱群のPBI値を觀察するに前者はやゝ高値を示し, また動物に発熱物質を連続投与した場合もPBIレベルの上昇をみとめた. 発熱物質單独投與後の末梢靜脈血ならびに甲状腺靜脈血中PBIレベルは, 早期一過性の低下を示し, 発熱物質の投與量および種類との間にはなんら一定の関係を見出しえず, 大体同じ傾向の変動を認めた. 甲状腺摘出犬ならびに肝障害犬を用いた実験では, これら末梢レベルの低下は, 主として甲状腺ホルモン末梢調節の主体をなす肝の活動の増加によるものであろうと推測される. なお発熱物質投與時の甲状腺ならびに副腎ホルモン分泌相は, 早期では拮抗的である.

1. Spontaneous mouse leukemia began to develop at 6 months and its maximum incidence was observed at 9 months of age.2. Of mice inoculated at less than 24 hours of age with cell-free filtrates extracted from AKR leukemic livers, spleens, and lymph nodes, 39.1% developed leukemia within 6 months. The incidence of leukemia for two groups of mice, 24 to 48 hours old and 48 to 72 hours old, was equally 25%. Very seldom leukemia resulted in mice inoculated at 6 to 48 days of age. There was a 2-month acceleration in the development of leukemia, however, in comparison with the control group.3. Whereas more females than males developed leukemia before 6 months following inoculation, after that time the reverse was the case.4. Leukemogenic activity of brain extracts was weaker than that of lymph node extracts.5. The second cell-free passage caused more leukemias than the first cell-free passage within 6 months.6. At autopsy there were two distinct types of leukemic involement, thymic and lymph node, and also transitional types of the two.7. The peripheral leukocyte count ranged in the majority of cases from 20, 000 to 30, 000per cu mm, rarely reaching 80, 000per cu mm. In differential counts, there were 1% to 52% lymphoblasts. Some leukemic mice showed an increase of cells of the neutrophilic series. Nucleated red cells were also present.8. In bone marrow, lymph node, thymus, and spleen, lymphoblasts were of the predominant cell type.9. In vitro tissue culture of lymph node, bone marrow, and spleen produced an identical growth pattern with that of acute lymphatic leukemia in human beings.10. The chromosomes studied in spontaneous AKR leukemia were 40 in number and rod-shaped, showing no aberrations from the normal counterparts.11. The first cell-free passage resulted in one of the mice in the development of myelogenous leukemia. The second cell-free passage from the myelogenous leukemia induced lymphatic leukemia in one of the mice injected.12. Lymphatic leukemia, once converted to the ascitic form, was subsequently maintained in the ascitic form by successive intraperitoneal transplantation.

ABS>The incidence of leukemia in RF mice exposed to a single whole-body irradiation of 350 r x-rays was 77.4%, in 41 out of 53 animals. In all, 20 developed the thymic and 20 the non-thymic lymphocytic leukemia, while only one developed myelogenous leukemia. The incidence of leukemia by 20- methylcholanthrene painting was 88% in 22 out of 25 animals. Of them, 12 developed lymphocytic leukemia and 10 myelogenous leukemia. Cell-free filtrates from the leukemic mice, which were induced by a single whole-body x irradiation, were inoculated to the newborn mice of the same strain less than 16 hours old. Two (18.7%) of the twelve inoculated animals developed leukemia on the 357th and 374th days, respectively, after the inoculation. Attempts to inoculate cell-free filtrate from 20-methylcholanthrene-induced leukemic RF mice to newborn mice of the same strain were successful. Cell-free filtrate from the myelogenous leukemic mouse caused lymphocytic leukemia in one of three inoculated mice. This is suggestive of the possibility of transformation of the type of leukemia during cell-free transmission. Virus-like particles were demonstrated by electron microscope in the lymph nodes of 20-methylcholanthrene-induced leukemic mice. The results suggest that x-ray and chemical carcinogens may act to induce leukemia or mammary carcinomamore » by the activation of a latent virus naturally resident in the RF mouse. (P.C.H.)« less

Uric acid transporter URAT1 contributes significantly to reabsorption of uric acid in humans to maintain a constant serum uric acid (SUA) level. Since alteration of SUA level is associated with various diseases, it is important to clarify the mechanism of change in SUA. However, although expression of mRNA of an ortholog of URAT1 (rUrat1) in rats has been reported, functional analysis and localization have not been done. Therefore, rat rUrat1 was functionally analyzed using gene expression systems and isolated brush-border membrane vesicles (BBMVs) prepared from rat kidney, and its localization in kidney was examined immunohistochemically. Uric acid transport by rUrat1 was chloride (Cl−) susceptible with a Km of 1773μM. It was inhibited by benzbromarone and trans-stimulated by lactate and pyrazinecarboxylic acid (PZA). Cl− gradient-susceptible uric acid transport by BBMVs showed similar characteristics to those of uric acid transport by rUrat1. Moreover, rUrat1 was localized at the apical membrane in proximal tubular epithelial cells in rat kidney. Accordingly, rUrat1 is considered to be involved in uric acid reabsorption in rats in the same manner as URAT1 in humans. Therefore, rUrat1 may be a useful model to study issues related to the role of human URAT1.