Distribution and metabolism in healthy volunteers of disodium azodisalicylate, a potential therapeutic agent for ulcerative colitis.

Abstract

SUMMARY A series of experiments has been performed in healthy male volunteers to investigate the disposition of orally administered disodium azodisalicylate, a potentially useful drug for the treatment of ulcerative colitis. The drug was given by mouth in doses of up to 2 g a day for six weeks and there were no adverse effects. Serum concentrations of the intact compound were low and the serum half-time was 4-12.8 days, probably because of a combination of a low clearance rate and a high apparent volume of distribution. Less than 5% of the ingested dose was excreted unchanged in the urine. Circulating concentrations of 5-ASA and N-acetyl-5-ASA were low and 30% of the equivalent daily dose was excreted in the urine, predominantly as N-acetyl-5-ASA. In most subjects more than 30% of the equivalent daily dose of 5-ASA was recovered from the faeces, either as 5-ASA itself or as the acetylated derivative. As 5-ASA has been shown to be the active therapeutic moiety of sulphasalazine, disodium azodisalicylate appears to be suitable for therapeutic trial in ulcerative colitis. Sulphasalazine (salicylazosulphapyridine) is well established as a valuable form of treatment for ulcerative colitis. It is of value in treating an acute attack of the disease1 2 and is especially useful as maintenance therapy for reducfrg the recurrence rate, which is lowered to about otie quarter of that in untreated subjects.34The mode of action of sulphasalazine is unknown but certain important aspects of its metabolism have been established. When taken by mouth (the usual form of administration) most of the drug reaches the colon intact and is there split by the colonic bacteria into sulphapyridine and 5-aminosalicylic acid (5-ASA). Virtually all the sulphapyridine is absorbed and is then excreted in the urine in conjugated form. Some of the 5-ASA is absorbed and is excreted in the urine as N-acetyl-5-ASA. A large proportion of the 5-ASA is excreted in the faeces.5A previous experiment in patients with ulcerative

Kinetics of 5‐aminosalicylic acid after jejunal instillation in man.

“…The human pharmacokinetics of 5-aminosalicylic acid (5-ASA) is only known from studies of Salazopyrin® (SASP) (Das et al, 1973(Das et al, , 1979Peppercorn & Goldman, 1973;Azad et al, 1982) sustained release preparations of 5-ASA (Rasmussen et al, 1982), 5-ASA contained in gelatin capsules (Schroder & Campbell, 1972), azodisalicylate (Willoughby et al, 1982), and 5-ASA given rectally (Fischer et al, 1983). The fate of pure 5-ASA has not previously been traced in man.…”

An oral preparation to release drugs in the human colon.

“…Another interesting development to deliver 5-ASA to the human colon involves two molecules of 5-ASA linked together with a diazo bond which would be split by bacteria in a similar way to sulphasalazine (Willoughby et al, 1981). The relative merits of our system compared with the one developed by Truelove and his colleagues must await further assessment.…”

Therapeutic Progress—reviewix.

“…5-arninosalicylic acid, its active split product, is absorbed too easily to give high colon levels when taken by mouth and is too unstable for a commercial enema preparation to be made. However, a dimer composed of two molecules of 5-aminosalicylic acid linked 'back-to-back' gives high faecal levels of 5-aminosalicylic acid when it is taken orally and so far seems to be free from adverse effects (134). Since this compound contains no sulphapyridine and is only poorly absorbed, it may be possible to greatly increase the concentration of 5-aminosalicylic acid attainable in the colon.…”