Pharmacokinetics in Wistar Rats of 5-(4-Carboxybutanoyl)Amino-2-Hydroxybenzoic Acid: A Novel Synthetic Derivative of 5-Aminosalicylic Acid (5-ASA) with Possible Anti-Inflammatory Activity

摘要

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).