Takeo Nakanishi

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• PhD
• Professor (Full) at Takasaki University of Health and Welfare

There is significant evidence that the inducible cyclooxygenase isoform (COX-2) regulates the pericellular concentration of PGE2; however, the mechanism of the secretory process remains unclear. The present study, therefore, aimed to evaluate the role of prostaglandin transporter (OATP2A1) in PGE2 secretion from macrophages. Immunofluorescence stai...

Prostaglandin (PG) E2 exhibits an anti-fibrotic effect in the lung in response to inflammatory reactions and is a high-affinity substrate of PG transporter (SLCO2A1). The present study aimed to evaluate the pathophysiological relevance of SLCO2A1 to bleomycin (BLM)-induced pulmonary fibrosis in mice. Immunohistochemical analysis indicated that Slco...

Breast cancer resistance protein (BCRP)/ATP-binding cassette subfamily G member 2 (ABCG2) is an ATP-binding cassette (ABC) transporter identified as a molecular cause of multidrug resistance (MDR) in diverse cancer cells. BCRP physiologically functions as a part of a self-defense mechanism for the organism; it enhances elimination of toxic xenobiot...

Solute carrier organic anion transporter family member 2A1 (SLCO2A1) is a prostaglandin (PG) transporter and serves as the osmosensitive ATP-permeable maxi-anion channel (Maxi-Cl). Since a heterotetrameric complex of annexin A2 (ANXA2) and S100A10 is obligatory for the channel activity; the present study aimed to determine if they regulate SLCO2A1-...

Nonalcoholic fatty liver disease (NAFLD) is a type of steatosis not associated with excessive alcohol intake and includes nonalcoholic steatohepatitis (NASH), which can progress to advanced fibrosis and hepatocellular carcinoma. Mitochondrial dysfunction causes oxidative stress, triggering hepatocyte death and inflammation; therefore, the present s...

SLCO2A1 functions as a prostaglandin (PG) influx transporter to facilitate intracellular oxidation of PGs and its defect causes dysregulation of PG signaling and metabolism. This study aimed to clarify effects of N-glycosylation on its functional expression. Putative N-glycosylation site(s) (N134, N478, and/or N491) of human SLCO2A1 were mutated to...

We evaluated the whole-body distribution of orally-administered radioiodine-125 labeled acetaminophen (125I-AP) to estimate gastrointestinal absorption of anionic drugs. 125I-AP was added to human embryonic kidney (HEK)293 and Flp293 cells expressing human organic anion transporting polypeptide (OATP)1B1/3, OATP2B1, organic anion transporter (OAT)1...

Chemoradiotherapy is frequently used to treat cancer. Stereotactic body radiotherapy (SBRT) is a single high-dose radiotherapy used to treat a variety of cancers. The anticancer drug methotrexate (MTX) shows affinity for solute carrier (SLC) and ATP-binding cassette (ABC) transporters. This study investigated relationships between accumulation of m...

Objective. Carbamazepine (CBZ), a widely used antiepileptic drug, is one major cause of the idiosyncratic liver injury along with immune reactions. Conversely, prostaglandin E 2 (PGE2) demonstrates a hepatoprotective effect by regulating immune reactions and promoting liver repair in various types of liver injury. However, the amount of hepatic PGE...

The prostaglandin (PG) transporter SLCO2A1 regulates PGE2 signaling and interacts with many drugs, and SLCO2A1 defects is associated with PG metabolic disorders. This study aimed to characterize a non-metabolic phenolsulfonphthalein (PSP) transport mediated by SLCO2A1. PSP uptake by HEK293 cells expressing human SLCO2A1 (HEK/2A1 cells) was pH-indep...

Gastrointestinal tract absorption of cationic anticancer drugs and medicines was estimated using whole-body imaging following oral [123I]MIBG administration. [123I]MIBG was added to cultures of human embryonic kidney (HEK)293 cells expressing human organic anion transporting polypeptide (OATP)2B1, carnitine/organic cation transporter (OCTN)1 and OC...

Plant-derived nanoparticles exert cytoprotective effects on intestinal cells by delivering their cargo to intestinal tissues. We previously reported that apple-derived nanoparticles (APNPs) downregulate themRNA of the human intestinal transporterOATP2B1/SLCO2B1and that the 3'UTR region is required for the response to APNPs. Here, we investigated th...

Introduction We clarified the renal uptake and urinary secretion mechanism of [99mTc]dimercaptosuccinic acid ([99mTc]DMSA) via drug transporters in renal proximal tubules. Methods [99mTc]DMSA was added to human embryonic kidney 293 cells expressing human multidrug and toxin extrusion (MATE)1 and MATE2-K, carnitine/organic cation transporter (OCTN)...

Solute carrier organic anion transporter family member 2A1 (SLCO2A1, also known as PGT, OATP2A1, PHOAR2, or SLC21A2) is a plasma membrane transporter consisting of 12 transmembrane domains. It is ubiquitously expressed in tissues, and mediates the membrane transport of prostaglandins (mainly PGE2, PGF2α, PGD2) and thromboxanes (e.g., TxB2). SLCO2A1...

Introduction ¹³¹I-labeled m-iodobenzylguanidine ([¹³¹I]MIBG) has been used to treat neuroblastoma patients, but [¹³¹I]MIBG may be immediately excreted from the cancer cells by the adenosine triphosphate binding cassette transporters, similar to anticancer drugs. The purpose of this study was to clarify the efflux mechanism of [¹³¹I]MIBG in neurobla...

Human OATP2B1, a member of organic anion transporting polypeptide family, is expressed in several tissues, including small intestine and liver, and contributes to cellular uptake of endogenous compounds and various drugs. Altered expression of OATP2B1 affects pharmacokinetics of substrate drugs; however, limited information is available on the regu...

We reported that bleomycin (BLM)-induced pulmonary fibrosis was exacerbated in the prostaglandin transporter gene (Slco2a1)-deficient mice (Slco2a1(−/−)). Because cigarette smoke (CS) contributes to creating a profibrotic milieu in the respiratory region, the present study aimed to investigate the impact of CS on SLCO2A1-associated pathogenesis in...

Inhibition of the apical sodium-dependent bile acid transporter (ASBT, also known as IBAT — ileal bile acid transporter, SLC10A2) leads to disruption of the enterohepatic circulation of bile acids and their excretion with fecal masses. This is accompanied by cholesterol utilization for synthesis of new bile acids. ASBT inhibitors are promising drug...

We evaluated the contribution of organic anion transporting polypeptide 2A1 (OATP2A1/SLCO2A1), a high-affinity carrier for prostaglandins (PGs), to the parturition process. At gestational day (GD) 15.5, OATP2A1 is co-localized with 15-hydroxy-PG dehydrogenase in the mouse placental junctional zone and facilitates PG degradation by delivering PGs to...

Loss-of-function mutations in the solute carrier organic anion transporter family, member 2a1 gene (SLCO2A1), which encodes a prostaglandin (PG) transporter, have been identified as causes of chronic nonspecific multiple ulcers in the small intestine; however, the underlying mechanisms have not been revealed. We, therefore, evaluated the effects of...

The acetylcholinesterase (AChE) inhibitor, acotiamide, improves gastric motility, and is clinically used to treat functional dyspepsia. The present study aimed to identify the transporters involved in the distribution of acotiamide in stomach tissue. Acotiamide uptake by the gastric cancer-derived model cell line, Hs746 T, was Na+- and pH-independe...

Prostaglandin E2 (PGE2) exhibits hepatoprotective effects against various types of liver injury. However, there is little information on the disposition of endogenous PGE2 during liver injury. In the present study, we attempted to elucidate the mechanism involved in regulating PGE2 distribution during liver injury. Carbon tetrachloride (CCl4) was u...

Technetium-99m-labeled mercaptoacetyltriglycine ([99mTc]MAG3) is widely used for evaluation of transplanted kidneys, diagnosis of tubular necrosis, and scintigraphic studies of tubular function. [99mTc]MAG3 is a substrate for organic anion transporter (OAT)1 and OAT3 on the basolateral membrane side for renal secretion. We investigated the transpor...

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

We examined whether [131I]6-β-iodomethyl-19-norcholesterol (NP-59), a cholesterol analog, can be used to measure function of hepatic drug transporters. Hepatic uptake of NP-59 with and without rifampicin was evaluated using HEK293 cells expressing solute carrier transporters. The stability of NP-59 was evaluated using mouse blood, bile, and liver,...

Prostaglandin E2 (PGE2) is a well-established chemical mediator for the generation of the fever at the hypothalamus of the brain. PGE2 mediates fever generation via PGE receptor 3 (i.e., EP3) on neurons in the preoptic area. The role of PGE2 has been analyzed by measuring PGE2 concentration in cerebrospinal fluid (Ccsf); however, local PGE2 concent...

The effects of hyperuricemia on the expression of kidney drug transporters and on the pharmacokinetics of several substrate drugs were examined. We first established a rat model of hyperuricemia without marked symptoms of chronic kidney failure by 10-day co-administration of oxonic acid (uricase inhibitor) and adenine (biosynthetic precursor of uri...

Relative mRNA expression levels of transporters in kidney of control and hyperuricemic rats (dataset of Fig 2). (DOCX)

Pharmacokinetic parameters of metformin, cephalexin and creatinine in control and hyperuricemic rats after intravenous administration of metformin or cephalexin (dataset of Table 2). (DOCX)

Plasma concentration and cumulative urinary excretion of cephalexin after administration of high (10 mg/kg) and low (1 mg/kg) doses (dataset of Fig 4). (DOCX)

Protein expression level of kidney Mate1 in control and hyperuricemic rats (dataset of Fig 5). (DOCX)

Primers for quantitative PCR. (DOCX)

Plasma concentration of uric acid in control rats and hyperuricemic rats during the 10-day administration period (dataset of Fig 1). (DOCX)

Pharmacokinetic parameters of cephalexin in control rats after intravenous administration of cephalexin (dataset of Table 3). (DOCX)

Effects of oxonic acid, adenine and uric acid on uptake of MPP+ by MATE1-expressing cells (dataset of Fig 6). (DOCX)

Plasma concentrations of BUN and creatinine and inulin clearance in control and hyperuricemic rats (dataset of Table 1). (DOCX)

Plasma concentrations of metformin, cephalexin and creatinine and cumulative urinary excretions of metformin, cephalexin and creatinine in control and hyperuricemic rats (dataset of Fig 3). (DOCX)

Kidney slice has been often used as a tool reflecting basolateral transport in renal tubular epithelial cells. Recently, we reported that several important apical reabsorptive transporters such as Octn1/2, Sglt1/2, and Pept1/2 were functional in mouse kidney slices as well as transporter activities in basolateral side, which have been well accepted...

Oxaliplatin is important for the clinical treatment of colorectal cancer and other gastrointestinal malignancies, but tumour resistance is limiting. Several oxaliplatin transporters were previously identified but their relative contributions to determining oxaliplatin tumour responses and gastrointestinal tumour cell sensitivity to oxaliplatin rema...

P‐glycoprotein (P‐gp, multidrug resistance 1 (MDR1)) overexpression confers multidrug resistance to cancer cells, and P‐gp in cell lines transfected with MDR1 or selected with chemotherapeutics significantly affect the anticancer drug efficacy. Although human cancer cell line panels consisting of defined tumor cell lines expressing endogenous P‐gp...

The inhibitor of uric acid reabsorptive transporter URAT1 in kidney is drawing attention as a drug target for hyperuricemia. However, it is difficult to evaluate efficacy of URAT1 inhibitors in vivo using laboratory animals due to species difference in uric acid metabolism. In the present study, the usefulness of exogenously administering uric acid...

Background Little is known about the affinity and stability of 99mTc-labeled 2-methoxyisobutylisonitrile (99mTc-MIBI) and tetrofosmin (99mTc-TF) for imaging of multiple drug resistance transporters in cancer. We examined the affinity of 99mTc-labeled compounds for these transporters and their stability. Methods 99mTc-MIBI and 99mTc-TF were incubat...

Prostaglandin transporter Oatp2a1/Slco2a1 is expressed at the apical (AP) membranes of type-1 alveolar epithelial (AT1) cells. To investigate the role of OATP2A1 in PGE2 handling by alveolar epithelium, we studied PGE2 transport across and secretion from monolayers of rat AT1-like (AT1-L) cells obtained by trans-differentiation of type-2 alveolar e...

Interaction of foods with intestinal transporters has generally been ascribed to small molecules, but recently, edible plant-derived nanoparticles (NPs) have been suggested to affect intestinal function. Here, we examined the effects of NPs contained in edible fruits on intestinal transporters. Apple-derived NPs (APNPs) were isolated by ultracentri...

Prostaglandin (PG) E2 is a well-established lipid mediator that plays a role in diverse functions and diseases of the brain. Cyclooxygenase and PGE synthase have been extensively studied as molecular determinants of extracellular concentration of PGE2 near prostanoid E receptors since the brain has limited capacity of PG metabolism. There is accumu...

Objectives: Little is known about the affinity of 99mTc-labeled 2-methoxyisobutylisonitrile (99mTc-MIBI) and tetrofosmin (99mTc-TF) for multiple drug resistance in cancer cells. Additionally, if 99mTc-labeled compounds are metabolized immediately after injection, imaging with these compounds may not allow monitoring of multiple drug resistance in c...

Creatinine is actively secreted across tubular epithelial cells via organic cation transporter 2 (OCT2) and multidrug and toxin extrusion 1 (MATE1). We previously showed that the tyrosine kinase inhibitor (TKI) crizotinib inhibits OCT2-mediated transport of creatinine. In the present work, we examined the inhibitory potency of TKIs, including crizo...

Prostaglandin E2 (PGE2 ) in the hypothalamus is a principal mediator of the febrile response. However, the role of organic anion transporting polypeptide 2A1 (OATP2A1/SLCO2A1), a prostaglandin transporter, in facilitating this response is unknown. Here, we investigated the effect of Slco2a1 deficiency on the body core temperature (Tc) and on the PG...

Drug food interaction is an important issue, since intake of food often alters pharmacokinetics and subsequently reduces efficacy and/or adverse effect of concurrently administered drugs. Although it has been reported that diet or beverage affects drug transporters and drug metabolizing enzymes, they were explained only by small molecules in foods....

Solute carrier organic anion transporter family member 2A1 (OATP2A1, encoded by the SLCO2A1 gene), which was initially identified as prostaglandin transporter (PGT), is expressed ubiquitously in tissues and mediates the distribution of prostanoids, such as PGE2, PGF2α, PGD2 and TxB2. It is well known to play a key role in the metabolic clearance of...

Breast cancer resistance protein (BCRP) overexpression confers multidrug resistance to cancer cells, and the efficacy of anticancer drugs has been reported to be significantly affected by BCRP in cell lines transfected with BCRP or selected with drugs. It is unclear whether the in vitro efficacy of anticancer drugs is affected by endogenous BCRP, a...

Prostaglandin E2 (PGE2) is associated with proliferation and angiogenesis in colorectal tumours. The role of prostaglandin transporter OATP2A1/SLCO2A1 in colon cancer tumorogenesis is unknown. We evaluated mice of various Slco2a1 genotypes in a murine model of colon cancer, the adenomatous polyposis (APC) mutant (Apc∆716/+) model. Median lifespan w...

Hepatic arterial infusion (HAI) chemotherapy is expected to be a more effective and safer method to treat the hepatic metastasis of pancreatic cancer than intravenous (i.v.) administration because of higher tumor exposure and lower systemic exposure. To clarify the uptake mechanism of nucleoside anticancer drugs, including gemcitabine (GEM), in pan...

Kidney plays a key role in the elimination and reabsorption of drugs and nutrients, however in vitro methods to evaluate renal disposition are limited. In the present study, we investigated usefulness of isolated kidney slice, which had been used for transport only at basolateral membrane of tubular epithelial cells, for evaluation of apical membra...

Trifluridine (FTD) exhibits anticancer activities after its oral administration despite its hydrophilic nature. We previously reported that concentrative nucleoside transporter (CNT) 1 mediates the apical uptake of FTD in human small intestinal epithelial cells (HIECs). In the present study, FTD was also identified as a substrate for equilibrative...

To understand interaction of drugs with the prostaglandin transporter OATP2A1/SLCO2A1 that regulates disposition of prostaglandins, we explored impacts of 636 drugs in an FDA-approved drug library on 6-carboxyfluorescein (6-CF) uptake by OATP2A1-expressing HEK293 cells (HEK/2A1). Fifty one and 10 drugs were found to inhibit and enhance 6-CF uptake...

The School of Pharmacy and Pharmaceutical Sciences at Trinity College Dublin hosted the 1stWorkshop on Drug Transporters in the Lungs in September 2016 to discuss the impact of transporters on pulmonary drug disposition and their roles as drug targets in lung disease. The workshop brought together about 30 scientists from academia and pharmaceutica...

The placenta is an organ that secretes prostaglandin (PG) E2 into the fetal-placental circulation to regulate both vascular tone and remodeling of the fetal ductus arteriosus. Placental PGE2 synthesis might be mediated by microsomal PGE synthase-1 (mPGES-1), in addition to cyclooxygenase (COX) isoforms. Thus, the purpose of this study is to clarify...

Skeletal muscle toxicity including rhabdomyolysis in severe case is a major side effect of LDL cholesterol-lowering statin drugs. We, therefore, aimed to explore microRNA (miRNA) expression to understand molecular mechanism of statin-induced toxicity. miRNA expression profiling assay for cerivastatin (1 μM for 48 hr)-treated RD cells showed more th...

This study aimed to investigate the interactions of three anti-coagulants, rivaroxaban, apixaban, and dabigatran, with five human SLC transporters, hOAT1, hOAT3, hOCT2, hOATP1B1, and hOATP1B3. Apixaban inhibited hOAT3, hOATP1B1, and hOATP1B3, and rivaroxaban inhibited hOAT3 and hOATP1B3, with IC50 values of > 20 and >5 μM, respectively. The effect...

Pharmacokinetic drug-drug interactions (DDIs) on hepatic organic anion transporting polypeptides (OATPs) are important clinical issues. Previously we reported that plasma dehydroepiandrosterone sulfate (DHEAS) could serve as an endogenous probe to predict OATP-based DDIs in monkeys using rifampicin as an OATP inhibitor. However, since the contribut...

Members of the organic anion transporting polypeptide (OATP) transporter family are involved in drug absorption and disposition, and therefore drug-drug and drug-food interactions at these transporters may have both pharmacological and toxicological effects. Accordingly, a detailed understanding of the substrates and modulators, including inhibitor...

Gene expression in different tissues is often controlled by alternative promoters that result in the synthesis of mRNA with unique — usually untranslated — first exons. Bcrp1 (Abcg2), the murine orthologue of the ABC transporter Breast Cancer Resistance Protein (BCRP, ABCG2), has at least four alternative promoters that are designated by the corres...

The goal of this study was to improve the intestinal mucosal cell membrane permeability of the poorly absorbed guanidino analogue of a neuraminidase inhibitor, oseltamivir carboxylate (GOC) using a carrier-mediated strategy. Valyl amino acid prodrug of GOC with isopropyl-methylene-dioxy linker (GOC-ISP-Val) was evaluated as the potential substrate...

Chronic inflammation induced by reactive oxygen species is associated with increased risk of developing colorectal cancer (CRC), and prostaglandin E2 (PGE2), which serves as a key mediator of inflammatory responses, plays an important role in CRC initiation and progression. Therefore, in the present study, we aimed to investigate the role of prosta...

Several drug transporters of the solute carrier (SLC and SLCO) and ATP binding cassette (ABC) families are expressed in the lung, and it is now known that active transport processes may affect the local pulmonary disposition of drugs administered directly to the lung, as well as being involved in the uptake of drugs to the lung from the systemic ci...

Oral bioavailability (F) is determined as fraction of the drug dose absorbed through the gastrointestinal membranes (Fa), the unmetabolized fraction of the absorbed dose that passes through the gut into the portal blood (Fg), and the hepatic first pass availability (Fh), namely F is expressed as the product of Fa, Fg and Fh (F = Fa x Fg x Fh). Curr...

Eicosapentaenoic acid (EPA)-derived prostaglandin E3 (PGE3) possesses an anti-inflammatory effect; however, information for transporters that regulates its peri-cellular concentration is limited. The present study, therefore, aimed to clarify transporters involved in local disposition of PGE3. PGE3 uptake was compared HEK293 cells transfected with...

Gastrointestinal (GI) toxicity, such as late-onset diarrhea, is a significant concern in irinotecan hydrochloride (CPT-11)-containing regimens. Prophylaxis of late-onset diarrhea has been reported with Japanese traditional (Kampo) medicine containing baicalin and with the antibiotic cefixime, and this has been explained in terms of inhibition of ba...

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To quantitatively understand the events in the human liver, we modeled a hepatic disposition of bosentan and its three known metabolites (Ro 48-5033, Ro 47-8634, and Ro 64-1056) in sandwich-cultured human hepatocytes based on the known metabolic pathway. In addition, the hepatotoxicity of Ro 47-8634 and Ro 64-1056 was investigated because bosentan...

Clinical reports indicate that cardiotoxicity due to donepezil can occur after co-administration with cilostazol. We speculated that the concentration of donepezil in heart tissue might be increased as a result of interaction with cilostazol at efflux transporters such as P-glycoprotein (P-gp, ABCB1) and BCRP (ABCG2), which are expressed in many ti...

Introduction: trans-1-Amino-3-[(18)F]fluorocyclobutanecarboxylic acid ([(18)F]fluciclovine, also known as anti-[(18)F]FACBC), is a tracer for positron emission tomography (PET) imaging for detection of tumors such as prostate cancer (PCa). Our previous study showed that ASCT2 (Na(+)-dependent amino acid transporter (AAT)) mediates fluciclovine upt...

Five-aminolevulinic acid (ALA) is a prodrug to generate phototoxic protoporphyrin IX (PPIX) for photodynamic cancer therapy. It remains unclear how PPIX accumulates in cancer cells; therefore, we aimed to clarify determinant factors by assessing ALA uptake, PPIX biosynthesis, conversion of PPIX to heme (ferrochelatase activity), and PPIX efflux, in...

Hepatic arterial infusion (HAI) chemotherapy with gemcitabine (GEM) is expected to be more effective and safer method to treat hepatic metastasis of pancreatic cancer compared with intravenous administration, because it affords higher tumor exposure with lower systemic exposure. Thus, a key issue for dose selection is the saturability of hepatic up...

TAS-102, which is effective for refractory metastatic colorectal cancer, is a combination drug of anticancer trifluridine (FTD; which is derived from pyrimidine nucleoside) and FTD-metabolizing enzyme inhibitor tipiracil hydrochloride (TPI) at a molecular ratio of 1:0.5. To evaluate the intestinal absorption mechanism of FTD, the uptake and transce...

Objectives It has been reported that intestinal urate excretion is increased at chronic kidney disease (CKD) state. In this report, whether uremic toxins are involved in the upregulation of intestinal breast cancer resistance protein (BCRP), an intestinal urate exporter, was examined.Methods Uremic toxins that were increased at least 15-fold at CKD...

We report a novel cyclic-AMP (cAMP) response element (CRE) in the human BCRP promoter that is functional in human cancer cell lines of multiple lineages. 8Br-cAMP increased the activity of a BCRP promoter reporter construct and BCRP mRNA in human carcinoma cells. Activation of the epidermal growth factor receptor (EGFR) pathway also led to an incre...

A lower exposure of mycophenolic acid (MPA) in patients receiving MPA-mofetil in combination with cyclosporin A (CsA) is thought to be due to the inhibition of enterohepatic circulation of phenyl-glucuronide of MPA (MPAG). This study aimed to evaluate the interaction of CsA with hepatic disposition of MPA and MPAG in sandwich-cultured human hepatoc...

Transporter proteins classified into the solute carrier (SLC) transporter superfamily are essential for import of nutrients required for cell survival in organisms. Various SLC transporters are differentially upregulated in cancer cells, and among them, polyspecific organic anion-transporting polypeptides (OATPs) have been proposed to have pathophy...

Estrone-3-sulfate (E1S) is thought to be a major estrogen precursor in estrogen receptor (ER)-positive breast cancer. Since E1S is a hydrophilic compound, the uptake of E1S into cancer cells is probably mediated by transporters, such as organic anion-transporting polypeptide (OATP, SLCO) family. In this study, we investigated the relationship betwe...

Sodium glucose cotransporter 2 (SGLT2) inhibitors have been reported to lower the serum uric acid (SUA) level. To elucidate the mechanism responsible for this reduction, we analyzed SUA and the urinary excretion rate of UA (UEUA) after the oral administration of luseogliflozin, an SGLT2 inhibitor, to healthy subjects. After dosing, SUA decreased, a...