Olsalazine

Olsalazine and its metabolite olsalazine-S, are more than 99% bound to plasma proteins. Less than 1% of both olsalazine and olsalazine-S appears undissociated in plasma. It does not interfere with the protein binding of warfarin. Mesalamine (5-aminosalicylic acid, 5-ASA) and its metabolite, N-acetyl-5-ASA, are 74 and 81%, respectively, bound to plasma proteins.

Olsalazine is an anti-inflammatory agent that blocks the production of cyclooxygenase (COX)-derived products of arachidonic acid metabolism. It works to alleviate inflammation in ulcerative colitis. Olsalazine was shown to decrease water and sodium absorption. While olsalazine is not expected to affect the motility and transit time of small intestines, it decreased small bowel transit time at high doses ranging from 60 to 120 mg/kg. In about 40% of the patients with ulcerative colitis, administration of olsalazine 1g daily was associated with a decrease in whole gut transit time.

Upon administration, the azo bond connecting two molecules of mesalamine (also known as 5-aminosalicylic acid or 5-ASA) is cleaved by azoreductase-containing bacteria in the colon. The two molecules of mesalamine are released to mediate therapeutic effects. The exact mechanism of action of olsalazine and its active moiety mesalamine in ulcerative colitis has not been elucidated; however, it is understood that mesalamine mediates an anti-inflammatory action on epithelial cells of the colon. The COX-derived (i.e., prostanoids such as prostaglandin E2) and lipoxygenase-derived products (i.e., leukotrienes [LTs] and hydroxyeicosatetraenoic acids [HETEs]) of arachidonic acid metabolism have been implicated in the pathogenesis and maintenance of inflammatory disorders, including ulcerative colitis and inflammatory bowel disease. Mesalamine may attenuate inflammation by blocking the COX enzyme and inhibiting prostaglandin production in the colon. Olsalazine was also shown to inhibit xanthine oxidase, an enzyme that generates oxygen-derived free radicals. Olsalazine may attenuate intestinal inflammation by limiting macrophage migration to inflamed intestinal mucosa: it was shown to inhibit _in vitro_ migration of intestinal macrophages in response to leukotriene B₄. Olsalazine may also act as a free radical scavenger, and mesalazine may suppress fatty acid peroxidation.

Olsalazine is cleaved by colonic bacteria to release its active ingredient, mesalamine. Mesalamine can undergo acetylation to form N-acetyl-5-aminosalicylic acid (N-acetyl-5-ASA, Ac-5-ASA) by the colonic epithelium; however, the extent of acetylation depends on transit time. Approximately 0.1% of an oral dose of olsalazine is metabolized in the liver to olsalazine-O-sulfate (olsalazine-S).

After oral administration, olsalazine has limited systemic bioavailability, with less than 5% of the oral dose being absorbed. Based on oral and intravenous dosing studies, approximately 2.4% of a single 1 g oral dose is absorbed. Maximum serum concentrations of olsalazine appear after approximately one hour and, even after a 1 g single dose, are low (e.g., 1.6 to 6.2 µmol/L). Patients on daily doses of 1 g olsalazine for two to four years show a stable plasma concentration of olsalazine-S (3.3 to 12.4 µmol/L). Olsalazine-S accumulates to a steady state within two to three weeks. Serum concentrations of mesalamine are detected after four to eight hours. The peak levels of mesalamine after an oral dose of 1 g olsalazine are low (i.e., 0 to 4.3 µmol/L).

Olsalazine and its metabolites are excreted in the urine. Total recovery of oral 14C-labeled olsalazine in animals and humans ranges from 90 to 97%. Approximately 20% of the total mesalamine is recovered in the urine. Of the total mesalamine found in the urine, more than 90% is N-acetyl-5-ASA. Only small amounts of mesalamine are detected in the urine. The remaining mesalamine is partially acetylated and excreted in the feces. From fecal dialysis, the concentration of mesalamine in the colon following olsalazine has been calculated to be 18 to 49 mmol/L. The urinary recovery of olsalazine is below 1%. Less than 5% of an oral dose (0.25 to 2g) was recovered unchanged in the feces; however, more than 50% of the oral dose was excreted in feces as unchanged olsalazine when the whole gut transit time was decreased by approximately 50%.

The steady-state volume of distribution determined in healthy volunteers is approximately 5L.