Abstract
5-[(4-carboxybutanoyl)amino]-2-hydroxybenzoic acid (C2) is a novel synthetic derivative of 5-aminosalicylic acid (5-ASA), which is currently being evaluated ex vivo as an anti-inflammatory agent and has shown satisfactory results. This study aimed to obtain the pharmacokinetic profiles, tissue distribution and plasma protein binding of C2 in Wistar Rats. Additionally, an HPLC method was developed and validated to quantify C2 in rat plasma. The pharmacokinetic profiles of intragastric, intravenous and intraperitoneal administration routes at singles doses of 100, 50, and 100 mg/kg, respectively, were studied in Wistar rats. The elimination half-life of intravenously administered C2 was approximately 33 min. The maximum plasma level of C2 was reached approximately 24 min after intragastric administration, with a Cmax value of 2.5 g/mL and an AUCtot value of 157 μg min-1/mL; the oral bioavailability was approximately 13%. Following a single intragastric or oral dose (100 mg/kg), C2 was distributed and detected in all examined tissues (including the brain and colon). The results showed that C2 accumulates over time. The plasma protein binding results indicated that the unbound fraction of C2 at concentrations of 1 to 20 μg/mL ranged from 89.8% to 92.5%, meaning that this fraction of C2 is available to cross tissues. Finally, the blood-plasma partitioning (BP ratio) of C2 in rat plasma was 0.71 and 0.6 at concentrations of 5 and 10 μg/mL, respectively, which indicates that C2 is free in the plasmatic phase and not inside blood cells. The results of this study suggest that a fraction of the administered C2 dose is absorbed in the stomach, and the fraction that is not absorbed reaches the small intestine and colon. This distribution constitutes the main advantage of C2 compared with 5-ASA for the treatment of ulcerative colitis (UC) and Crohn's disease (CD).
Highlights
Inflammatory bowel disease (IBD) is the medical term used to describe chronic inflammatory diseases of the gastrointestinal tract (GI) that are characterized by a wide range of signs and symptoms, such as diarrhea, abscesses, fistulas, abdominal pain and stenosis
A batch of 5-[(4-carboxybutanoyl) amino]-2-hydroxybenzoic acid (C2) was synthesized at the Laboratorio de Investigación en Química Orgánica y Supramolecular de la Unidad Profesional Interdisciplinaria de Biotecnología; the molecular structure of C2 was validated using infrared spectroscopy, 1H nuclear magnetic resonance spectroscopy and 13C and mass spectrometry; these analyses were conducted by the Centro de Nanociencias y Micro y Nanotecnología-IPN
For C2 quantification in plasma and other tissues, a RP-high performance liquid chromatography (HPLC) method with UV-Vis detection was first developed, and the validation demonstrated that this method is suitable and complies with the performance parameters established by the FDA and ICH regulations for bioanalytical methods
Summary
Inflammatory bowel disease (IBD) is the medical term used to describe chronic inflammatory diseases of the gastrointestinal tract (GI) that are characterized by a wide range of signs and symptoms, such as diarrhea, abscesses, fistulas, abdominal pain and stenosis. These symptoms significantly affect the quality of life of affected patients [1, 2]. UC inflammation typically arises in the distal colon and extends in a proximal direction [3,4,5,6]. Both CD and UC are characterized by periods of active intestinal inflammation that may require hospitalization [1, 2, 5, 7, 8]
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