The therapeutic effects and metabolism of mesalazine (5-aminosalicylic acid) in patients with inflammatory bowel disease require intracellular accumulation of the drug in intestinal epithelial cells and hepatocytes. The molecular mechanisms of mesalazine uptake into cells have not been characterized so far. Using human embryonic kidney cells stably expressing uptake transporters of the organic anion-transporting polypeptide (OATP) family, which are expressed in human intestine and/or liver, we found that mesalazine uptake is mediated by OATP1B1, OATP1B3, and OATP2B1 but not by OATP1A2 and OATP4A1. Moreover, genetic variations (*1b, *5, *15) in the SLCO1B1 gene encoding OATP1B1 reduced the K(m) value for mesalazine uptake from 55.1 to 16.3, 24.3, and 32.4 μM, respectively, and the respective V(max) values. Finally, budesonide, cyclosporine, and rifampin were identified as inhibitors of OATP1B1-, OATP1B3-, and OATP2B1-meditated mesalazine uptake. These in vitro data indicate that OATP-mediated uptake and its modification by genetic factors and comedications may play a role for mesalazine effects.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1124/dmd.110.034991 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Mucoadhesive Mesalamine Prodrug Nanoassemblies to Target Intestinal Macrophages for the Treatment of Inflammatory Bowel Disease.
ACS Nano
June 2024
Medicinal Materials Research Center, Biomedical Research Division, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea.
While mesalamine, a 5-aminosalicylic acid (5-ASA), is pivotal in the management of inflammatory bowel disease (IBD) through both step-up and top-down approaches in clinical settings, its widespread utilization is limited by low bioavailability at the desired site of action due to rapid and extensive absorption in the upper gastrointestinal (GI) tract. Addressing mesalamine's pharmacokinetic challenges, here, we introduce nanoassemblies composed exclusively of a mesalamine prodrug that pairs 5-ASA with a mucoadhesive and cathepsin B-cleavable peptide. In an IBD model, orally administered nanoassemblies demonstrate enhanced accumulation and sustained retention in the GI tract due to their mucoadhesive properties and the epithelial enhanced permeability and retention (eEPR) effect.
View Article and Find Full Text PDFDownregulation of OATP2B1 by proinflammatory cytokines leads to 5-ASA hyposensitivity in Ulcerative colitis.
Chem Biol Interact
August 2024
Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, China; Department of Gastroenterology, The Third People's Hospital of Yuhang District, Hangzhou, China; Westlake Laboratory of Life Sciences and Biomedicine of Zhejiang Province, Hangzhou, China. Electronic address:
5-Aminosalicylic acid (5-ASA) is a first-line agent in both remission and maintenance therapy for ulcerative colitis (UC). However, the mucosal concentration of 5-ASA was significantly lower in patients with severe histological inflammation, which further led to a poor response to 5-ASA treatment. Our study aimed to clarify the mechanism of 5-ASA uptake into colonic epithelial cells and to further explore the reason for the decreased colonic mucosal 5-ASA concentration in UC patients.
View Article and Find Full Text PDFCardiac sarcoidosis in a patient with ulcerative colitis: A case report and literature review.
Medicine (Baltimore)
January 2024
Division of Gastroenterology, Department of Internal Medicine, Asahikawa Medical University, Asahikawa, Japan.
Article Synopsis
- The text discusses a case of a 71-year-old woman with ulcerative colitis (UC) who was later diagnosed with cardiac sarcoidosis, indicating a link between the two chronic inflammatory diseases.
- It highlights the potential risk of cardiac sarcoidosis in UC patients and emphasizes the importance of monitoring for symptoms that could indicate this complication.
- The patient was successfully treated with prednisolone and methotrexate, resulting in the resolution of symptoms and abnormal findings, underscoring the need for regular cardiac evaluations in UC patients.
Optimization, cellular uptake, and in vivo evaluation of Eudragit S100-coated bile salt-containing liposomes for oral colonic delivery of 5-aminosalicylic acid.
Int J Pharm
December 2023
Drug Delivery and Nano Pharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan. Electronic address:
Eudragit S100-coated bile salt-containing liposomes were prepared and optimized by experimenting with different variables, including bile salt type and concentration, and the method of incorporation into liposomes using a model hydrophilic compound, 5-aminosalicylic acid (5-ASA). After optimizing the formulation, cellular uptake, and animal pharmacokinetic experiments were performed. The inclusion of sodium glycocholate (SG) into liposomes decreased liposome particle size and entrapment efficiency significantly but had no effect on zeta potential.
View Article and Find Full Text PDFpH-sensitive HPMCP-chitosan nanoparticles containing 5-aminosalicylic acid and berberine for oral colon delivery in a rat model of ulcerative colitis.
Int J Biol Macromol
July 2023
The Novel Drug & Vaccine Delivery Systems Facility, Department of Chemistry and Biochemistry, Laurentian University, Sudbury, ON P3E 2C6, Canada. Electronic address:
Ulcerative colitis (UC) with continuous and extensive inflammation is limited to the colon mucosa and can lead to abdominal pain, diarrhea, and rectal bleeding. Conventional therapies are associated with several limitations, such as systemic side effects, drug degradation, inactivation, and limited drug uptake, leading to poor bioavailability. These restrictions necessitate drug delivery to the colon so that the drug passes through the stomach unchanged and has selective access to the colon.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!