Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1.    Pharmacodynamic Properties
Around 90% of a dose reaches the colon where bacteria split the drug into sulfapyridine (SP) and mesalazine (ME). These are active, and the unsplit sulfasalazine (SASP) is also active on a variety of symptoms. Most SP is absorbed, hydroxylated or glucuronidated and a mix of unchanged and metabolised SP appears in the urine. Some ME is taken up and acetylated in the colon wall, such that renal excretion is mainly ac-me. SASP is excreted unchanged in the bile and urine. Overall, the drug and its metabolites exert immunomodulatory effects, antibacterial effects, effects on the arachidonic acid cascade and alteration of activity of certain enzymes. The net result clinically is a reduction in activity of the inflammatory bowel disease. The enteric coated SASP is registered for the treatment of rheumatoid arthritis, where the effect resembles penicillamine or gold.

In rheumatoid arthritis a disease modifying effect is evident in 1-3 months, with characteristics falls in CRP and other indicators of inflammation. ME is not believed to be responsible for this effect.

For EN-tabs, radiographic studies show marked reduction in progression (larsen or sharp index) compared with placebo or hydroxychloroquine over two years in early patients. If drug is stopped the benefit appears to be maintained.

Pharmacokinetic Properties

5.2.    Pharmacokinetic properties

Studies with En-tabs show no statistically significant differences in main parameters compared with an equivalent dose of SASP powder, and the figures produced below relate to ordinary tablets. With regard to the use of salazopyrin in bowel disease there is no evidence that systemic levels are of any relevance other than with regard to ADR incidence. Here levels of SP over about 50µg/ml are associated with a substantial risk of ADRs, especially in slow acetylators.
For SASP given as a single 3g oral dose, peak serum levels of SASP occurred in 3-5 hours, elimination half life was 5.7 ±0.7 hours, lag time 1.5 hours. During maintenance therapy renal clearance of SASP was 7.3 ±1.7ml/min, for SP 9.9 ±1.9 and AC-ME 100 ±20. Free SP first appears in plasma in 4.3 hours after a single dose with an absorption half life of 2.7 hours. The elimination half life was calculated as 18 hours.
Turning to mesalazine, in urine only AC-ME (not free ME) was demonstrable, the acetylation probably largely achieved in the colon mucosa. After a 3g SASP dose lag time was 6.1 ±2.3 hours and plasma levels kept below 2µg/ml total ME. Urinary excretion half-life was 6.0 ±3.1 hours and absorption half life based on these figures 3.0 ±1.5 hours. Renal clearance constant was 125 ml/min corresponding to the GFR.

With regard to rheumatoid arthritis there is no data which suggests any differences from those above.