Olsalazine

The mechanism of action of mesalamine (and sulfasalazine) is unknown, but appears to be topical rather than systemic. Mucosal production of arachidonic acid (AA) metabolites, both through the cyclooxygenase pathways (i.e., prostanoids) and through the lipoxygenase pathways (i.e., leukotrienes [LTs] and hydroxyeicosatetraenoic acids [HETEs]) is increased in patients with chronic inflammatory bowel disease, and it is possible that mesalamine diminishes inflammation by blocking cyclooxygenase and inhibiting prostaglandin (PG) production in the colon.

After oral administration, olsalazine has limited systemic bioavailability. Based on oral and intravenous dosing studies, approximately 2.4% of a single 1.0 g oral dose is absorbed. Less than 1% of olsalazine is recovered in the urine. The remaining 98 to 99% of an oral dose will reach the colon, where each molecule is rapidly converted into two molecules of 5-aminosalicylic acid (5-ASA) by colonic bacteria and the low prevailing redox potential found in this environment. The liberated 5-ASA is absorbed slowly resulting in very high local concentrations in the colon.

The conversion of olsalazine to mesalamine (5-ASA) in the colon is similar to that of sulfasalazine, which is converted into sulfapyridine and mesalamine. It is thought that the mesalamine component is therapeutically active in ulcerative colitis (A.K. Azad-Kahn et al, LANCET, 2:892-895, 1977). The usual dose of sulfasalazine for maintenance of remission in patients with ulcerative colitis is 2 grams daily, which would provide approximately 0.8 gram of mesalamine to the colon. More than 0.9 gram of mesalamine would usually be made available in the colon from 1 gram of olsalazine.

The pharmacokinetics of olsalazine are similar in both healthy volunteers and in patients with ulcerative colitis. Maximum serum concentrations of olsalazine appear after approximately 1 hour and, even after a 1.0 g single dose, are low (e.g., 1.6 to 6.2 µmol/L). Olsalazine has a very short serum half-life, approximately 0.9 hour. Olsalazine is more than 99% bound to plasma proteins. It does not interfere with protein binding of warfarin. The urinary recovery of olsalazine is below 1%. Total recovery of oral ¹⁴C-labeled olsalazine in animals and humans ranges from 90 to 97%. Approximately 0.1% of an oral dose of olsalazine is metabolized in the liver to olsalazine-O-sulfate (olsalazine-S). Olsalazine-S, in contrast to olsalazine has a half-life of 7 days. Olsalazine-S accumulates to steady state within 2 to 3 weeks.

Patients on daily doses of 1.0 g olsalazine for 2 to 4 years show a stable plasma concentration of olsalazine-S (3.3 to 12.4 µmol/L). Olsalazine-S is more than 99% bound to plasma proteins. Its long half-life is mainly due to slow dissociation from the protein binding site. Less than 1% of both olsalazine and olsalazine-S appears undissociated in plasma.

5-aminosalicylic acid (5-ASA)

Serum concentrations of 5-ASA are detected after 4 to 8 hours. The peak levels of 5-ASA after an oral dose of 1.0 g olsalazine are low (i.e., 0 to 4.3 µmol/L). Of the total 5-ASA found in the urine, more than 90% is in the form of N-acetyl-5-ASA (Ac-5-ASA). Only small amounts of 5-ASA are detected.

N-acetyl-5-ASA (Ac-5-ASA), the major metabolite of 5-ASA found in plasma and urine, is acetylated (deactivated) in at least two sites, the colonic epithelium and the liver. Ac-5-ASA is found in the serum, with peak values of 1.7 to 8.7 µmol/L after a single 1.0 g dose. Approximately 20% of the total 5-ASA is recovered in the urine, where it is found almost exclusively as Ac-5-ASA. The remaining 5-ASA is partially acetylated and is excreted in the feces. From fecal dialysis, the concentration of 5-ASA in the colon following olsalazine has been calculated to be 18 to 49 mmol/L. No accumulation of 5-ASA or Ac-5-ASA in plasma has been detected. 5-ASA and Ac-5-ASA are 74 and 81%, respectively, bound to plasma proteins.

Preclinical subacute and chronic toxicity studies in rats have shown the kidney to be the major target organ of olsalazine toxicity. At an oral daily dose of 400 mg/kg or higher, olsalazine treatment produced nephritis and tubular necrosis in a 4-week study; interstitial nephritis and tubular calcinosis in a 6-month study, and renal fibrosis, mineralization, and transitional cell hyperplasia in a 1-year study.