Pharmacokinetics of 5-aminosalicylic acid in man following administration of intravenous bolus andper os slow-release formulation

Abstract

The fate of 5-aminosalicylic acid (5-ASA), which is used in the treatment of chronic inflammatory bowel diseases, was studied in six healthy volunteers receiving doses of 100 mg and 250 mg intravenous bolus as well as 250 mg per os (slow release). Following intravenous administration, the drug was rapidly eliminated with a plasma half-life of about 40 min, mainly due to rapid metabolism. No parent drug was recovered in feces, and the total recovery following oral administration (30%) was significantly lower than following the intravenous doses (77% and 72%). Nonlinear pharmacokinetics were suggested as the 2.5-fold increase in intravenous dose was followed by a significant relative increase (greater than 2.5) in the renal elimination of 5-ASA, as well as a significant decrease (less than 2.5) in the elimination of the metabolite N-acetyl-5-ASA. There was also a trend towards a decreasing total body clearance and metabolic ratio. The present study confirms earlier findings on the pharmacokinetics of 5-ASA and suggests a possible saturation of the N-acetylating system in the dose range studied. This may be of interest in the design of controlled-release formulations and dosage regimes for the treatment of diseases of the small-bowel, where 5-ASA is easily absorbed. Further, for the first time, a marked difference in the intestinal fate compared to the systemic fate of the drug is demonstrated, suggesting alternative presystemic metabolism of 5-ASA, which may bear relevance to its mode of action. Further studies on the pharmacokinetics of 5-ASA, preferably in patients, are warranted.

Mesalazine pharmacokinetics and NAT2 phenotype

“…Mesalazine release from this formulation has been reported to occur throughout the gastrointestinal tract [19]. It has a bioavailability of approximately 30 % [18] which is lower than that of gastroresistant tablets and may be in part be caused by a more extensive intestinal first pass metabolism which is saturable [7] (see also Table 1). Indeed, in vitro studies showed that homogenates of colonic mucosa [8] and more specifically the cytosol of human colonic epithelial cells are able to mediate mesalazine Nacetylation [20].…”

“…Because of the short elimination half-life of mesalazine of clearly less than 3 hours [1,7], a prolonged release preparation is needed for maintaining plasma concentrations during a dosing interval, but also for direct delivery to any intestinal site of action. Mesalazine release from this formulation has been reported to occur throughout the gastrointestinal tract [19].…”

“…While acetylation of sulfapyridine, a known NAT2 substrate, was polymorphic, this could not be shown for mesalazine [6]. Mesalazine pharmacokinetics did also not co-segregate with NAT2 activity as assessed by sulfadimidine, but the respective study was conducted in 6 subjects only [7]. Furthermore, under saturation conditions for mesalazine, no relationship of ex vivo mucosal N-acetylation of mesalazine to systemic Nacetylation of sulfapyridine following systemic administration of sulfasalazine was found [8].…”

Mesalazina: profilo farmacologico, terapeutico e farmacoeconomico

“…Le diverse formulazioni orali di mesalazina comportano una biodisponibilità sistemica media variabile dal 20% al 30%, con un elevato grado di variabilità interindividuale [20,21]. Qualora la mesalazina venga rilasciata precocemente nel primo tratto dell'intestino, la biodisponibilità può aumentare sensibilmente In questo lavoro, dopo aver tracciato in sintetico profilo farmacologico clinico e terapeutico della mesalazina, esamineremo anche la sua rilevanza da un punto di vista farmacoeconomico nel trattamento delle IBD.…”

Simple and sensitive spectrophotometric methods for the analysis of mesalamine in bulk and tablet dosage forms

“…[1][2][3][4] Mesalamine has the chemical name 5-amino-2-hydroxybenzoic acid; its structural formula is given in Figure 1. Mesalamine is thought to be the major therapeutically active part of the sulfasalazine molecule in the treatment of ulcerative colitis.…”