Study of the plasma pharmacokinetics and faecal excretion of the prodrug olsalazine and its metabolites after oral administration to horses

Abstract

Olsalazine sodium (Dipentum*) has been used therapeutically against inflammatory bowel disease in human medicine as an alternative to sulphasalazine over the past 20 years. Bacteria in the colon split this prodrug into two molecules of the locally effective 5-aminosalicylic acid (5-ASA). Considering the potential therapeutic use in equine colitis, the pharmacokinetics of olsalazine (OLZ) after single oral administration to six horses at a dosage of 30 mg/kg was investigated. Plasma concentrations of OLZ, 5-ASA, and its main metabolite N-acetyl-5-aminosalicylic acid (Ac-5-ASA) were analysed by high-performance liquid chromatography methods. Evaluation of the plasma pharmacokinetics revealed a rapid, but low extent of absorption of OLZ (peak concentrations around 1 microg/mL at 0.5-1.5 h), and a delayed minimal absorption of 5-ASA (concentrations < 0.2 microg/mL, at 11-35 h), which is immediately metabolized to Ac-5-ASA. As indicators of the local availability in the colon, high faecal water concentrations of 5-ASA and Ac-5-ASA (mean C(max) about 300 and 130 microg/mL, respectively), but only traces of OLZ were found in faeces excreted 18-50 h after dosing. Of the administered OLZ dose 26% could be recovered from faeces, almost completely as 5-ASA and Ac-5-ASA. Routine clinical examination of the horses and assay of standard haematological and serum chemistry parameters before and after OLZ administration confirmed that a single dosage of 30 mg/kg was well tolerated. To estimate the systemic availability of 5-ASA liberated from OLZ, 5-ASA was administered i.v. at a dosage of 1.5 mg/kg to four horses and plasma concentrations of 5-ASA and Ac-5-ASA were determined. The pharmacokinetic evaluation showed a very low bioavailability of 2.4% for 5-ASA, released from orally administered OLZ. Furthermore, in an in vitro experiment, the metabolic transformation of 5-ASA to Ac-5-ASA mediated by bacteria in the caecal content of horses was determined at 38 degrees C for 31 h and compared with the metabolism data of the in vivo study. The markedly lower degree of acetylation in vitro supports the assumption that biotransformation of 5-ASA in vivo occurs not only by colonic bacteria, but also at other sites.

Management of Chronic Diarrhea in an Adult Horse

“…This drug is a colon-specific prodrug commonly used for the treatment of inflammatory bowel diseases such as ulcerative colitis and Crohn disease in humans, as well in veterinary medicine (eg, eosinophilic colitis in dogs or cats and typhlocolitis in horses) [7]. Its mode of action is not well understood.…”

“…Its mode of action is not well understood. The anti-inflammatory effect of the drug is probably because of inhibition of eicosanoid metabolism, and the interaction of 5-ASA with oxygen-derived free radicals is considered to be an essential mechanism of its effect [7]. The dosage was adapted based on the values commonly used in small animal practice (16 mg/kg PO once a day for 5 days, followed by 8 mg/kg PO once a day for 10 days) [8].…”

Degradability of the linear azo polymer conjugated 5,5′‐azodisalicylic acid segment in the main chain for colon‐specific drug delivery

“…The running conditions of HPLC were similar to those reported by Knoll et al 7 The mobile phase consisted of a mixture of 0.1M acetic acid and 0.4% (v/v) triethylamine (pH 4.3) with acetonitrile in the ratio of 89.5 : 10.5 (v/v). Before analysis, the mobile phase was filtered (0.45 lm) and degassed by means of an ultrasonic bath.…”

“…Site-specific delivery to the colon can be achieved by the exploitation of the specific microbial enzyme activities (e.g., azoreductase) present in the colon. The azoreductase activities in the colonic fluid can be used to convert low-molecular-weight prodrugs into active metabo-lites [4][5][6][7] and to release active species from water-soluble polymeric carriers. [8][9][10][11][12][13][14] Recently, we studied the synthesis and properties of a novel type of linear azo polymer for colon-specific drug delivery.…”

The treatment of diarrhoea in the adult horse

“…The treatment of diarrhoea in the adult horse inflammatory treatment in human ulcerative colitis patients (Nikfar et al 2008). Prodrugs that have been evaluated in the horse, such as olsalazine, showed limited clinical applicability due to poor bioavailability and biotransformation at locations other than the colon (Knoll et al 2002). A newer preparation, mesalamine, has shown improved pharmacokinetics and may have a potential use in horses with chronic diarrhoea and ongoing mucosal damage, following appropriate clinical trials (Karagozian and Burakoff 2007).…”