Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1    Pharmacodynamic Properties
Pharmacotherapeutic group: Intestinal anti-inflammatory agents, aminosalcylic acid and similar agents
ATC Code: A07 EC02
Mechanism of action and pharmacodynamic effects:
Mesalazine is the active component of sulphasalazine which has been used for a long time in the treatment of ulcerative colitis and Crohn's disease.
The therapeutic value of mesalazine appears to be due to local effect on the inflamed intestinal tissue, rather than to systemic effect. There is information suggesting that severity of colonic inflammation in ulcerative colitis patients treated with mesalazine is inversely correlated with mucosal concentrations of mesalazine.
Increased leucocyte migration, abnormal cytokine production, increased production of arachidonic acid metabolites, particularly leukotriene B4 and increased free radical formation in the inflamed intestinal tissue are all present in patients with inflammatory bowel disease. The mechanism of action of mesalazine is not fully understood although mechanisms such as activation of the γ-form of peroxisome proliferator-activated receptors (PPAR-γ) and inhibition of nuclear factor-kappa B (NF-κB) in the intestinal mucosa have been implicated. Mesalazine has in-vitro and in-vivo pharmacological effects that inhibit leucocyte chemotaxis, decrease cytokine and leukotriene production and scavenge for free radicals. It is currently unknown which, if any of these mechanisms play a predominant role in the clinical efficacy of mesalazine.
The risk of colorectal cancer (CRC) is slightly increased in ulcerative colitis.
Observed effects of mesalazine in experimental models and patient biopsies support the role of mesalazine in prevention of colitis-associated CRC, with down regulation of both inflammation dependent and non-inflammation dependent signalling pathways involved in the development of colitis-associated CRC. However data from meta- analyses, including both referral and non-referral populations, provide inconsistent clinical information regarding the benefit of mesalazine in the carcinogenesis risk associated with ulcerative colitis.

Pharmacokinetic Properties

5.2    Pharmacokinetic Properties
General Characteristics of the Active Substance
Disposition and local availability:
The therapeutic activity of mesalazine most likely depends on a local contact of the drug with the diseased area of the intestinal mucosa.
Pentasa slow release granules consist of ethylcellulose coated microgranules of mesalazine. The coated microgranules enter the duodenum within an hour of administration, independent of food co-administration. Mesalazine is continuously released from the coated microgranules throughout the gastrointestinal tract in any enteral pH conditions.
Absorption: Bioavailability of Pentasa after oral administration can be estimated to approx.. 30%, based on urine recovery data in healthy volunteers. Maximum plasma concentrations are seen 1-6 hours post-dose. A once-daily dosing regimen of mesalazine (1 × 4 g/d) and a twice-daily dosage (2 × 2 g/d) results in a comparable systemic exposure (AUC) over 24 hours and indicate a continuous release of mesalazine from the formulation over the treatment period. Steady-state is reached after a treatment period of 5 days following oral administration.
Single dose                        Steady state
Mesalazine         Cmax (ng/mL) AUC 0-24              Cmax (ng/mL) AUC 0-24 (h·ng/mL)                           (h·ng/mL)
2 g BID            5103.51           36,456           6803.70            57,519
4 g OD             8561.36           35,657           9742.51            50,742
Molecular weight of mesalazine: 153.13 g/moL; Ac-mesalazine: 195.17 g/moL.

The transit and release of mesalazine after oral administration are independent of food co-administration, whereas the systemic exposure may be increased.
Distribution: Mesalazine and acetyl mesalazine do not cross the blood-brain barrier.
Protein binding of mesalazine is approximately 50% and of acetyl mesalazine about 80%.
Metabolism: Mesalazine is metabolised both pre-systemically by the intestinal mucosa and systemically in the liver to N-acetyl-mesalazine (acetyl-mesalazine) principally by NAT-1. Some acetylation also occurs through the action of colonic bacteria. The acetylation seems to be independent of the acetylator phenotype of the patient. The metabolic ratio of acetyl-mesalazine to mesalazine in plasma after oral administration ranges from 3.5 to 1.3 after daily doses of 500 mg×3 and 2 g×3, respectively, implying a dose-dependent acetylation which may be subject to saturation.
Elimination: Due to continuous release of mesalazine throughout the gastrointestinal tract, the elimination half-life cannot be determined after oral administration.
However, once the formulation is not present in the GI tract elimination will follow the plasma half-life of orally or IV administered uncoated mesalazine, which is approximately 40 minutes and for acetyl-mesalazine approximately 70 minutes.
Characteristics in patients:
Pathophysiologic changes such as diarrhoea and increased bowel acidity observed during active inflammatory bowel disease have only a minor impact on the delivery of mesalazine to the intestinal mucosa after oral administration. A urine excretion 20- 
25% of the daily dose has been observed in patients with accelerated intestinal transit.
Likewise, a corresponding increase in faecal excretion has been seen.