Preclinical Pharmacokinetics and Acute Toxicity in Rats of 5-{[(2E)-3-Bromo-3-carboxyprop-2-enoyl]amino}-2-hydroxybenzoic Acid: A Novel 5-Aminosalicylic Acid Derivative with Potent Anti-Inflammatory Activity.

Compound 5-{[(2E)-3-bromo-3-carboxyprop-2-enoyl]amino}-2-hydroxybenzoic acid (C1), a new 5-aminosalicylic acid (5-ASA) derivative, has proven to be an antioxidant in vitro and an anti-inflammatory agent in mice. The in vivo inhibition of myeloperoxidase was comparable to that of indomethacin. The aim of this study was to take another step in the preclinical evaluation of C1 by examining acute toxicity with the up-and-down OECD method and pharmacokinetic profiles by administration of the compound to Wistar rats through intravenous (i.v.), oral (p.o.), and intraperitoneal (i.p.) routes. According to the Globally Harmonized System, C1 belongs to categories 4 and 5 for the i.p. and p.o. routes, respectively. An RP-HPLC method for C1 quantification in plasma was successfully validated. Regarding the pharmacokinetic profile, the elimination half-life was approximately 0.9 h with a clearance of 24 mL/min after i.v. administration of C1 (50 mg/kg). After p.o. administration (50 mg/kg), the maximum plasma concentration was reached at 33 min, the oral bioavailability was about 77%, and the compound was amply distributed to all tissues evaluated. Therefore, C1 administered p.o. in rats is suitable for reaching the colon where it can exert its effect, suggesting an important advantage over 5-ASA and indomethacin in treating ulcerative colitis and Crohn's disease.

In vitro release kinetics of graft matrices from Lannea coromandelica (Houtt) gum for treatment of colonic diseases by 5-ASA.

Polyacrylamide graft Jhingan gum (Jh-g-PAMs) was synthesized adopting microwave assisted graft co-polymerization technique. The synthesized graft copolymer was characterized by various analytical techniques such as Elemental analysis, FTIR, TGA, XRD and NMR. Following standard protocol, drug matrix tablets using 5-Aminosalicylic Acid (5-ASA) were prepared and swelling and erosion studies were carried out in different pH dissolution media. The result revealed that maximum swelling and erosion took place in pH 7.4 while the lowest was recorded in pH 1.2. The 'in vitro' drug release studies revealed that grades with higher grafting % exhibited more sustained release. The highest sustained release was observed in Jh-g-PAM 3 (%G 1231) in pH 1.2 while the least was observed in native gum in pH 7.4. Furthermore, the kinetic studies revealed that 'n' values in all dissolution media lies within 0.5-1.0 which suggested non-Fickian diffusion mode of release. From the above results, it can be said that controlled release of 5-ASA using graft material was successful and hence it can be explored for treatment of colon related diseases.

Pharmacokinetics of Para-Aminosalicylic Acid and Its 2 Major Metabolites: A Potential Relationship to the Development of Gastrointestinal Intolerance.

Para-aminosalicylic acid (PAS), often the last drug remaining for treatment of drug-resistant tuberculosis, is notorious for causing gastrointestinal intolerance; however, the cause of PAS intolerance is uncertain. The objective of this study was to assess relationships between peak concentrations of PAS administered as a granular slow-release enteric coated formulation, and its metabolites acetyl-PAS and glycine-PAS, and intolerance. PAS and its metabolites were measured in 29 adult patients with drug-resistant tuberculosis at Brooklyn Hospital, Cape Town, randomized to receive granular slow-release enteric-coated PAS 4 g twice daily or 8 g once daily for 1 week, followed by the alternative regimen. Concentrations of PAS and its metabolites were determined by liquid chromatography and tandem mass spectrometry, and a visual analogue scale evaluated intolerance. Spearman's correlation test assessed the relationship between maximum plasma concentrations (Cmax ) and intolerance scores. A large interindividual variability was observed for the PAS Cmax (40.42-68.55 mg/L) following 4 g twice daily; (62.69-102.41 mg/L) for 8 g once daily and a similar wide Cmax range found for the metabolites acetyl-PAS and glycine-PAS. Twenty-six patients reported at least 1 intolerance episode, but most visual analogue scale scores clustered around 0. Significant inverse associations were found between acetyl-PAS Cmax and bloating (rho = -0.448; P = .025) and diarrhea (rho = -0.407; P = .044) for the twice-daily regimen and a similar inverse association found for glycine-PAS and diarrhea (rho = -0.412; P = .041). Plasma concentrations of the metabolites did not correlate with the occurrence of gastrointestinal symptoms, but higher metabolite concentrations correlated with lower intolerance scores; slow metabolism of PAS and its continued presence in the intestinal tract may be the main cause of intolerance.

Technetium-99 m labeling and evaluation of olsalazine: a novel agent for ulcerative colitis imaging.

Ulcerative colitis is a chronic disease having a regressive nature. Commonly used diagnostic methods have the disadvantage to be invasive, time-consuming, and expensive. Therefore, a new sensitive method for the detection and monitoring of disease activity is urgently needed in clinical practice. In the current investigation, radio complexation of olsalazine with technetium-99m, its characterization, and optimization of the labeling conditions were explored. Optimum radiochemical yield of (99m) Tc-olsalazine (97.6% ± 1.8%) was obtained via direct complexation with technetium-99m (~200 MBq) in the presence of stannous chloride dihydrate (100 µg) as reducing agent at pH 6. It was observed that the complex showed significant in vitro stability in serum at 37°C for more than 11 h. The computer-generated optimized geometries of the (99m) Tc-olsalazine were reported, and biodistribution studies were carried out using chemically and microbiologically mice-induced ulcerative colitis models. The tracer showed a good localization in both models and was excreted mainly via liver and to some extent via kidney. Imaging can be performed at 1-2 h post-injection; at that time, the background activity has cleared, and the activity is concentrated in the target site. All the gathered biological data supported the usefulness of (99m) Tc-olsalazine as a potential imaging agent for ulcerative colitis.

Roles of P-glycoprotein and multidrug resistance protein in transporting para-aminosalicylic acid and its N-acetylated metabolite in mice brain.

AIM: Para-aminosalicylic acid (PAS) is effective in the treatment of manganism-induced neurotoxicity (manganism). In this study we investigated the roles of P-glycoprotein (MDR1a) and multidrug resistance protein (MRP) in transporting PAS and its N-acetylated metabolite AcPAS through blood-brain barrier. METHODS: MDR1a-null or wild-type mice were intravenously injected with PAS (200 mg/kg). Thirty minutes after the injection, blood samples and brains were collected, and the concentrations of PAS and AcPAS in brain capillaries and parenchyma were measured using HPLC. Both MDCK-MDR1 and MDCK-MRP1 cells that overexpressed P-gp and MRP1, respectively, were used in two-chamber Transwell transport studies in vitro. RESULTS: After injection of PAS, the brain concentration of PAS was substantially higher in MDR1a-null mice than in wild-type mice, but the brain concentration of AcPAS had no significant difference between MDR1a-null mice and wild-type mice. Concomitant injection of PAS with the MRP-specific inhibitor MK-571 (50 mg/kg) further increased the brain concentration of PAS in MDR1a-null mice, and increased the brain concentration of AcPAS in both MDR1a-null mice and wild-type mice. Two-chamber Transwell studies with MDCK-MDR1 cells demonstrated that PAS was not only a substrate but also a competitive inhibitor of P-gp, while AcPAS was not a substrate of P-gp. Two-chamber Transwell studies with the MDCK-MRP1 cells showed that MRP1 had the ability to transport both PAS and AcPAS across the BBB. CONCLUSION: P-gp plays a major role in the efflux of PAS from brain parenchyma into blood in mice, while MRP1 is involved in both PAS and AcPAS transport in the brain.

Effect of quercetin on the transport of N-acetyl 5-aminosalicylic acid.

OBJECTIVES: The aim of this study was to investigate the transporter-mediated transport of N-acetyl 5-aminosalicylic acid (Ac-5-ASA) and the effect of quercetin on Ac-5-ASA transport. METHODS: Caco-2 cell monolayers grown in Transwells were used to study the transport of Ac-5-ASA in the absence or presence of quercetin, and apical-to-basolateral and basolateral-to-apical apparent permeability (PappAB and PappBA values, respectively) was determined. The effect of transporter inhibitors, such as MK571, quinidine and mitoxantrone, on the transport of Ac-5-ASA was investigated. KEY FINDINGS: In the absence of transporter mediators, the transport of Ac-5-ASA was much higher in the basolateral-to-apical direction than in the opposite direction. The PappBA/PappAB ratio of Ac-5-ASA was 4.89. Quercetin inhibited the apical efflux of Ac-5-ASA and decreased the PappBA/PappAB ratio to 1.05. Of the transporter inhibitors, MK571 decreased the PappBA/PappAB ratio to 1.07; however, neither quinidine nor mitoxantrone had an effect on Ac-5-ASA transport. CONCLUSIONS: Ac-5-ASA was excreted by multidrug resistance-associated protein 2 from Caco-2 cells, and its transport was inhibited by quercetin. Our findings suggest that dose levels of sulfasalazine or 5-aminosalicylic acid can be decreased by coadministration of quercetin, leading to improved pharmaceutical care for inflammatory bowel diseases.

Aminosalicylates.

Aminosalicylates are the most common drugs for the primary treatment of inflammatory bowel disease. Various pro-drugs and formulations were developed in order to improve pharmacological profiles, optimize bioavailability and to gain highest efficacy in the treatment of ulcerative colitis (UC) and Crohn's disease. In vitro studies have greatly contributed to the understanding of the molecular actions in vivo and clinical studies have proven aminosalicylates to be effective and safe. This review summarizes the current knowledge on the molecular, pharmacological and clinical properties of aminosalicylates with respect to chemoprevention for UC-associated colorectal cancer.

Brain regional pharmacokinetics of p-aminosalicylic acid and its N-acetylated metabolite: effectiveness in chelating brain manganese.

para-aminosalicylic acid (PAS; 4-amino-2-hydroxybenzoic acid), an antituberculosis drug in use since the 1950s, has recently been suggested to be an effective agent for treatment of manganese-induced parkinsonian disorders. However, the neuropharmacokinetics of PAS and its metabolite N-acetyl-para-aminosalicylic acid (AcPAS; N-acetyl-4-amino-2-hydroxybenzoic acid) are unknown. This study was designed to investigate the pharmacokinetics of PAS and its distribution in brain to help better design the dosing regimen for clinical trials. Male Sprague-Dawley rats received single femoral artery injections of PAS (200 mg/kg). Plasma, cerebrospinal fluid, and brain tissues were collected, and PAS and AcPAS concentrations were quantified by high-performance liquid chromatography. After administration, the concentrations of PAS declined rapidly in plasma with an elimination t(½) of 34 min; the metabolite AcPAS was detected in plasma and eliminated with a t(½) of 147 min. PAS and AcPAS were detected in brain tissues; AcPAS had a much higher tissue concentration and a longer t(½) than the parent PAS in most tissues examined. Although both were present in blood or tissues as free, unbound molecules, AcPAS appeared to have a higher tissue affinity than PAS. Taken together, our results suggest that a dosing regimen with continuous intravenous infusion of PAS is necessary to achieve therapeutic levels in targeted brain regions. Furthermore, PAS and AcPAS seem to be effective in reducing manganese levels in brain.

Determination of 3-methoxysalicylamine levels in mouse plasma and tissue by liquid chromatography-tandem mass spectrometry: application to in vivo pharmacokinetics studies.

We report the development of a sensitive liquid chromatography-tandem mass spectrometric assay to quantitate 3-methoxysalicylamine (3-MoSA) in biological samples. Derivatization with 1,1'-thiocarbonyldiimidazole followed by C(18) reverse-phase chromatography allowed the detection of both analyte and internal standard (hexylsalicylamine) using electrospray ionization and selected reaction monitoring (SRM) in positive ion mode. We monitored the transitions from m/z 196.7 to 65.1 and from m/z 250.1 to 77.1 for 3-MoSA and HxSA, respectively. The method is validated with respect to linearity (r(2)=0.995), precision (<17% RSD), recovery (100% for 3-MoSA and HxSA), and stability (77% after storage up to 7 month at -80°C). The LOD and LOQ were 16.12 and 48.87 µg/l, respectively and the LLOQ of 1 pg/ml. In addition, we used this assay to analyze the pharmacokinetics of 3-MoSA in mouse plasma and tissues following both intraperitoneal and oral administration, providing new information regarding the distribution of this compound in vivo.

[Mesalazine old and new]. / Mesalazinas viejas, mesalazinas nuevas.

Aminosalycylates (5-ASA) are still the drugs of choice both for mild-to-moderate outbreaks of ulcerative colitis and to maintain long-term remission. The efficacy of these drugs has been widely demonstrated in placebo-controlled trials. However, when administered orally, their pharmacological characteristics hamper the desired therapeutic effect. Currently, efficiency can be optimized by exclusive or combined rectal administration. The present article reviews the available data on the efficacy of galenic preparations of 5-ASA and discusses the potential advantages of galenic forms of 5-ASA coated with a novel multi-matrix delivery system.

Clinical pharmacology of 5-ASA compounds in inflammatory bowel disease.

Mesalamine has been the first-line of therapy in patients with inflammatory bowel disease (IBD) since the 1960s. This article serves as a review of the different 5-aminosalicylic acid compounds, release formulations, use and dosing in the treatment of IBD, in particular ulcerative colitis.

High thiopurine metabolite concentrations associated with lymphopenia in inflammatory bowel disease (IBD) pediatric patients receiving aminosalicylates combined with azathioprine.

OBJECTIVE: Aminosalicylates are widely used with azathioprine in the treatment of IBD. The association results in an increase in 6-TGN levels in adults with IBD with a difference in the occurrence of myelotoxic effects. Scarce data are available in pediatric population. We proposed to investigate the effect of the coadministration of aminosalicylates on thiopurine concentrations in pediatric IBD patients. MATERIALS AND METHODS: Data from 71 patients treated for at least 1 y by azathioprine and aminosalicylates were recorded. 6-TGN and 6-MeMPN concentrations, blood cell counts and liver function tests were compared between patients taking and those not taking aminosalicylates. RESULTS: Aminosalicylate therapy was associated with a significant increase in mean 6-TGN but also 6-MeMPN concentrations. In patients in remission, 6-TGN level was related to aminosalicylate dosage (r = 0.561, p = 0.010). Lymphopenia rate was higher in patients receiving combined therapy compared to monotherapy whereas a slight rise in leucopenia was found. CONCLUSIONS: This observation suggests that the higher frequency of lymphopenia may be associated with the elevated 6-TGN concentrations recovered in patients treated with aminosalicylates. This combination does not improve remission rate but could increase adverse effects especially lymphopenia.

Chitosan/Kollicoat SR 30D film-coated pellets of aminosalicylates for colonic drug delivery.

The purpose of the study was to (i) prepare the chitosan/Kollicoat SR 30D film-coated pellets for colonic drug delivery, and (ii) evaluate the colonic delivery and efficacy of these coated pellets in the rat. The pellets were coated to different film thickness with chitosan/Kollicoat SR 30D formulations. In vitro drug release was assessed in simulated gastrointestinal (GI) tract conditions. Biodistribution of aminosalicylates (5-ASA) in GI tract and plasma was measured after oral administration of coated or uncoated 5-ASA pellets. Efficacy of the coated or uncoated 5-ASA pellets was tested in 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced rat colitis model. Healing of induced colitis was assessed by measuring the myeloperoxidase activities, colon wet weight/body weight, and damage score. The coating was susceptible to bacteria digestion, resulting in an increase in the release of 5-ASA from the coated pellets. After administration of the coated pellets, the drug concentration in the large intestine was higher than those of uncoated pellets. In plasma, the observed mean C(max) from the coated pellets was significantly lower than that of the uncoated pellets. Chitosan/Kollicoat SR 30D film-coated pellets could deliver the 5-ASA to the targeted site, providing effective treatment for inflammatory bowel disease.

Inhibitory effect of flavonoids on the efflux of N-acetyl 5-aminosalicylic acid intracellularly formed in Caco-2 cells.

N-acetyl 5-aminosalicylic acid (5-AcASA) that was intracellularly formed from 5-aminosalicylic acid (5-ASA) at 200 microM was discharged 5.3, 7.1, and 8.1-fold higher into the apical site than into the basolateral site during 1, 2, and 4-hour incubations, respectively, in Caco-2 cells grown in Transwells. The addition of flavonols (100 microM) such as fisetin and quercetin with 5-ASA remarkably decreased the apically directed efflux of 5-AcASA. When 5-ASA (200 microM) was added to Caco-2 cells grown in tissue culture dishes, the formation of 5-AcASA decreased, and, in addition, the formed 5-AcASA was found to be accumulated within the cells in the presence of such flavonols. Thus, the decrease in 5-AcASA efflux by such flavonols was attributed not only to the inhibition of N-acetyl-conjugation of 5-ASA but to the predominant cellular accumulation of 5-AcASA. Various flavonoids also had both of the effects with potencies that depend on their specific structures. The essential structure of flavonoids was an absence of a hydroxyl substitution at the C5 position on the A-ring of flavone structure for the inhibitory effect on the N-acetyl-conjugation of 5-ASA, and a presence of hydroxyl substitutions at the C3' or C4' position on the B-ring of flavone structure for the promoting effect on the cellular accumulation of 5-AcASA. Both the decrease in 5-AcASA apical efflux and the increase in 5-AcASA cellular accumulation were also caused by MK571 and indomethacin, inhibitors of MRPs, but not by quinidine, cyclosporin A, P-glycoprotein inhibitors, and mitoxantrone, a BCRP substrate. These results suggest that certain flavonoids suppress the apical efflux of 5-AcASA possibly by inhibiting MRPs pumps located on apical membranes in Caco-2 cells.

Safety, efficacy, and pharmacokinetics of balsalazide in pediatric patients with mild-to-moderate active ulcerative colitis: results of a randomized, double-blind study.

OBJECTIVES: : A multicenter, double-blind study was conducted to evaluate the safety, efficacy, and pharmacokinetics of balsalazide in pediatric patients with mild-to-moderate ulcerative colitis (UC). PATIENTS AND METHODS: : Sixty-eight patients, 5 to 17 years of age, with mild-to-moderate active UC based on the modified Sutherland UC activity index (MUCAI) were randomized to receive oral balsalazide 2.25 or 6.75 g/day for 8 weeks. The primary endpoint was clinical improvement (reduction of the MUCAI score by > or =3 points from baseline). Clinical remission (MUCAI score of 0 or 1 for stool frequency) and histological improvement after 8 weeks were also assessed. Pharmacokinetic parameters for balsalazide, 5-aminosalicylic acid, and N-acetyl-5-aminosalicylic acid were determined at 2 weeks. Adverse events and laboratory changes were monitored throughout the study. RESULTS: : Clinical improvement was achieved by 45% and 37% of patients and clinical remission by 12% and 9% of patients receiving 6.75 and 2.25 g/day, respectively. Improvement in histologic grade was achieved by 8 of 16 (50%) and 3 of 10 (30%) patients receiving 6.75 and 2.25 g/day, respectively. No significant differences were seen in efficacy. Pharmacokinetics in 12 patients were characterized by large interpatient variability and low systemic exposure. Adverse events were similar between the treatment groups, the most common being headache and abdominal pain. No clinically significant changes were observed in laboratory values, including those indicative of hepatic or renal toxicity. CONCLUSIONS: : Balsalazide is well tolerated and improves the signs and symptoms of mild-to-moderate active UC in pediatric patients 5 to 17 years of age.

Colon-specific mutual amide prodrugs of 4-aminosalicylic acid for their mitigating effect on experimental colitis in rats.

Mutual amide prodrugs of 4-aminosalicylic acid with D-phenylalanine and L-tryptophan were synthesized for targeted drug delivery to the inflamed gut tissue in inflammatory bowel disease. Stability studies in aqueous buffers (pH 1.2 and 7.4) showed that the synthesized prodrugs were stable in both the buffers over a period of 10 h. In rat fecal matter the release of 4-aminosalicylic acid from the prodrugs was in the range of 86-91% over a period of 20 h, with half-lives ranging between 343 and 412 min following first order kinetics. Targeting potential of the carrier system and the ameliorating effect of the amide conjugates were evaluated in trinitrobenzenesulfonic acid-induced experimental colitis model in rats. The prodrugs were assessed for their probable damaging effects on pancreas and liver with the help of histopathological analysis and for their ulcerogenic potential by Rainsford's cold stress method. They were found to have improved safety profile than sulfasalazine, oral 4- and 5-aminosalicylic acid with similar pharmacological spectrum and advantages of sulfasalazine.

Development and validation of a HPLC-ESI-MS/MS method for the determination of 5-aminosalicylic acid and its major metabolite N-acetyl-5-aminosalicylic acid in human plasma.

A new HPLC method for the determination of 5-aminosalicylic acid (5-ASA) and N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA) in human plasma was developed and validated. Plasma samples were analyzed after protein precipitation with methanol and the two analytes were separated using a C18 column with a mobile phase composed of 17.5 mmol/L acetic acid (pH 3.3):acetonitrile=85:15 (v/v) at 0.2 mL/min flow rate. 4-ASA and N-Ac-4-ASA were used as internal standards. Selective detection was performed by tandem mass spectrometry with electrospray source, operating in negative ionization mode and in multiple reaction monitoring acquisition (m/z 152-->108 for 5-ASA; m/z 194-->150 and 194-->107 for N-Ac-5-ASA). The limit of quantification (LOQ) was 50 ng/mL for both analytes (0.2 ng injected) and matrix-matched standard curves showed linearity up to 4000 ng/mL. In the entire analytical range the within- and between-batch precision (R.S.D.%) values were respectively < or = 6.3% and < or = 11% for 5-ASA and < or = 8.0% and < or = 10% for N-Ac-5-ASA. For both analytes the within- and between-batch accuracy (bias%) values ranged respectively from -8.4% to 7.9% and from -7.9% to 8.0%. The overall recoveries (n=6) at three tested concentration levels (i.e. 100, 1000 and 4000 ng/mL) were respectively >90% for 5-ASA and >95% for N-Ac-5-ASA (R.S.D.% < or = 10%). The method was applied to evaluate the pharmacokinetic of 5-ASA after a single oral dose administration of this compound (1200 mg) to 24 healthy volunteers. The mean maximum concentration levels were 680 ng/mL for 5-ASA and 1240 ng/mL for N-Ac-5-ASA and the kinetic profiles were in agreement with previous studies.

Synthesis and properties of N,N'-bis(5-aminosalicyl)-L-cystine as a colon-specific deliverer of 5-aminosalicylic acid and cystine.

N,N(')-bis(5-aminosalicyl)-L-cystine (5-ASA-Cys) was prepared by a simple synthetic route. 5-ASA-Cys was not degraded in pH 1.2 and 6.8 buffer solutions, and in the homogenates of the upper intestine. In marked contrast, 5-ASA-Cys was deconjugated extensively to liberate 5-ASA in the cecal contents. Upon oral administration of 5-ASA-Cys to rats, the plasma concentration of 5-ASA-Cys was extremely low and the urinary recovery of 5-ASA-Cys was approximately 10% of the dose. These results suggest that 5-ASA-Cys administered orally is delivered efficiently to the large intestine followed by deconjugation to liberate 5-ASA and cystine.

Synthesis, kinetic studies and pharmacological evaluation of mutual azo prodrug of 5-aminosalicylic acid for colon-specific drug delivery in inflammatory bowel disease.

Mutual azo prodrug of 5-aminosalicylic acid with l-tyrosine was synthesized by coupling l-tyrosine with salicylic acid, for targeted drug delivery to the inflamed gut tissue in inflammatory bowel disease. The structure was confirmed by elemental analysis, IR and NMR spectroscopy. In vitro kinetic studies in rat fecal matter showed 87.18% release of 5-aminosalicylic acid with a half-life of 140.28min, following first order kinetics. Therapeutic efficacy of the carrier system and the mitigating effect of the azo conjugate were evaluated in trinitrobenzenesulfonic acid-induced experimental colitis model. Myeloperoxidase activity was determined by the method of Krawisz et al. The synthesized prodrug was found to produce comparable mitigating effect as that of sulfasalazine on colitis in rats.

Transport of nicotinate and structurally related compounds by human SMCT1 (SLC5A8) and its relevance to drug transport in the mammalian intestinal tract.

UNLABELLED: PURPOSE. To examine the involvement of human SMCT1, a Na+-coupled transporter for short-chain fatty acids, in the transport of nicotinate/structural analogs and monocarboxylate drugs, and to analyze its expression in mouse intestinal tract. MATERIALS AND METHODS: We expressed human SMCT1 in X. laevis oocytes and monitored its function by [14C]nicotinate uptake and substrate-induced inward currents. SMCT1 expression in mouse intestinal tract was examined by immunofluorescence. RESULTS: [14C]Nicotinate uptake was several-fold higher in SMCT1-expressing oocytes than in water-injected oocytes. The uptake was inhibited by short-chain/medium-chain fatty acids and various structural analogs of nicotinate. Exposure of SMCT1-expressing oocytes to nicotinate induced Na+-dependent inward currents. Measurements of nicotinate flux and associated charge transfer into oocytes suggest a Na+:nicotinate stoichiometry of 2:1. Monocarboxylate drugs benzoate, salicylate, and 5-aminosalicylate are also transported by human SMCTI. The transporter is expressed in the small intestine as well as colon, and the expression is restricted to the lumen-facing apical membrane of intestinal and colonic epithelial cells. CONCLUSIONS: Human SMCTI transports not only nicotinate and its structural analogs but also various monocarboxylate drugs. The transporter is expressed on the luminal membrane of the epithelial cells lining the intestinal tract. SMCT1 may participate in the intestinal absorption of monocarboxylate drugs.