Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Intestinal anti-inflammatory agents, Aminosalicylic acid and similar agents 
ATC code: A07EC02
Mechanism of action
The mechanism of the anti-inflammatory action is unknown. The results of in-vitro studies indicate that inhibition of lipoxygenase may play a role.
Effects on prostaglandin concentrations in the intestinal mucosa have also been demonstrated.
Mesalazine (5-Aminosalicylic acid/5-ASA) may also function as a radical scavenger of reactive oxygen compounds.
Pharmacodynamic effects
Mesalazine, orally administered, acts predominantly locally at the gut mucosa and in the submucous tissue from the luminal side of the intestine. It is important, therefore, that mesalazine is available at the regions of inflammation. Systemic bioavailability/plasma concentrations of mesalazine therefore are of no relevance for therapeutic efficacy, but rather a factor for safety. In order to fulfil these criteria, Rafassal Caplets are coated with Eudragit L; they are thus gastro-resistant and release of mesalazine is pH- 

dependent.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties
General considerations of mesalazine
Absorption
Mesalazine absorption is highest in proximal gut regions and lowest in distal gut areas.
Biotransformation
Mesalazine is metabolised pre-systemically both by the intestinal mucosa and the liver to the pharmacologically inactive N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA). The acetylation seems to be independent of the acetylator phenotype of the patient. Some acetylation also occurs through the action of colonic bacteria. Protein binding of mesalazine and N-Ac-5-ASA is 43% and 78%, respectively.
Elimination
Mesalazine and its metabolite N-Ac-5-ASA are eliminated via the faeces (major part), renally (varies between 20 and 50%, dependent on kind of application, pharmaceutical preparation and route of mesalazine release, respectively) and biliary (minor part). Renal excretion predominantly occurs as N-Ac- 5-ASA.
About 1% of total orally administered mesalazine dose is excreted into the breast milk mainly as N-Ac-5- ASA.
Caplets/Tablets specific
Distribution
A combined pharmacoscintigraphic/pharmacokinetic study showed that 500mg tablets (Salofalk ®), reach the ileocoecal region after approximately 3-4 hours in fasting subjects and reach the ascending colon within approximately 4–5 hours.
The total transit time in the colon is approximately 17 hours
Absorption
Release of mesalazine from 500mg tablets (Salofalk ®) begins after a lag-phase of approximately 3–4 hours. Peak plasma concentrations are reached after approximately 5 hours (ileocoecal region) and, at 3 x 500 mg mesalazine/ day under steady-state conditions, are 3.0 ± 1.6 mcg/ml for mesalazine and 3.4 ± 1.6 mcg/ml for the metabolite, N-Ac-5-ASA.
Release of mesalazine from 1g tablets (Salofalk ®) begins after a lag-phase of approximately 4 hours. Peak plasma concentrations of mesalazine are reached after 8 hours and are 2.5 ± 3.4 mcg/ml for mesalazine and 2.5 ± 2.4 mcg/ml for the metabolite, N-Ac-5-ASA, after single dose administration.

Elimination
The total renal elimination rate for mesalazine and N-Ac-5-ASA over 24 hours during multiple intake (3 x 1 500 mg tablets, for 2 days; 1 tablet on the third day=examination day) was approximately 60%. The non- metabolised mesalazine fraction after oral administration was approximately 10%.