Salofalk Mechanism of Action

Pharmacotherapeutic Group: Aminosalicylic acid and similar agents. ATC Code: A07EC02.
The mode of action to date is still not understood. It is, however, interesting that both salicylazosulfapyridine and 5-aminosalicylic acid inhibit prostaglandin synthesis and that prostaglandin-like substances appear in the feces and venous blood of the colon in ulcerative colitis. Prostaglandins are involved in inflammatory processes.
Hence, it has been suggested that salicylazosulfapyridine inhibits prostaglandin synthesis and reduces the breakdown of these substances. It is not as yet known which prostanoid is affected.
Pharmacology: Pharmacodynamics: Mechanism of Action: Granules: 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.
Mesalazine, orally administered, acts predominantly locally at the gut mucosa and in the submucosal 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 are therefore of no relevance for therapeutic efficacy, but rather a factor for safety. In order to realize this, Salofalk granules are gastric juice resistant and release mesalazine in a pH dependent manner, due to an Eudragit L coating and prolonged manner, due to the matrix granule structure.
Pharmacokinetics: General Considerations of Mesalazine: Absorption: Mesalazine absorption is highest in the proximal regions and lowest in the distal regions of the intestine.
Biotransformation: Mesalazine is metabolised pre-systemically to the pharmacologically inactive N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA) in both the intestinal mucosa and the liver. Acetylation appears to be independent of the patient's acetylator phenotype. Some of the mesalazine is also acetylated by the bacteria of the large intestine. 43% of mesalazine and 78% of N-Ac-5-ASA are protein-bound.
Elimination/Excretion: Mesalazine and its metabolite N-Ac-5-ASA, are excreted in the faeces (major fraction), renally (the amount varies between 20% and 50%, depending on the method of administration, the pharmaceutical form and the associated mode of release of mesalazine) and via the biliary route (minor fraction). Renal excretion is mainly in the form of N-Ac-5-ASA. Approximately 1% of the orally administered mesalazine dose passes into breast milk, mainly as N-Ac-5-ASA.
Tablet: Absorption: Mesalazine absorption is highest in the proximal regions and lowest in the distal regions of the intestine.
Biotransformation: Mesalazine is metabolised pre-systematically to the pharmacologically inactive N-acetyl-5-aminosalicylic (N-Ac-5-ASA) in both the intestinal mucosa and the liver. Acetylation appears to be dependent on the patient's acetylator phenotype. Some of the mesalazine is also acetylated by the bacteria of the large intestine. 43% of mesalazine and 78% of N-Ac-5-ASA are protein-bound.
Elimination/Excretion: Mesalazine and its metabolite N-Ac-5-ASA, are excreted in the faeces (major fraction), renally (the amount varies between 20% and 50%, depending on the method of administration, the pharmaceutical form and the associated mode of release of mesalazine) and via the biliary route (minor fraction). Renal excretion is mainly in the form of N-Ac-5-ASA. Approximately 1% of the orally administered mesalazine dose passes into breast milk, mainly as N-Ac-5-ASA.
Specific aspects of Salofalk 500 mg gastro-resistant tablets: Distribution: A combined pharmacoscintigraphic/pharmacokinetic study has shown that in fasting patients, Salofalk 500 mg gastro-resistant tablets reach the ileocoecal region within approximately 3-4 hours in fasting subjects and the ascending colon within approximately 4-5 hours. In the colon, the total transit time is around 17 hours.
Absorption: Release of mesalazine from Salofalk 500 mg gastro-resistant tablets begins after a lag phase of approximately 3–4 hours. Peak plasma concentrations are reached after approximately 5 hours (ileocoecal region), and are 3.0 ±1.6 μg/mL for mesalazine and 3.4 ±1.6 μg/mL for the N-Ac-5-ASA metabolite following administration of 3 x 500 mg mesalazine/day under steady-state conditions.
Elimination: With multiple dosing (3 x 1 Salofalk 500 mg gastro-resistant tablets taken over 2 days; 1 gastro-resistant tablet on the third day = day of investigation), the total renal elimination rate of mesalazine and N-Ac-5-ASA over 24 hours was approximately 60%. When administered orally, the non-metabolised mesalazine fraction was approximately 10%.
Salofalk Granules Specific: Distribution: Owing to the granule size of approximately 1 mm, transit from the stomach to the small intestine is fast. A combined pharmacoscintigraphic/pharmacokinetic study showed that the compound reaches the ileocaecal region within approximately 3 hrs and the ascending colon within approximately 4 hrs. The total transit time in the colon amounts to about 20 hrs.
Approximately 80% of an administered oral dose is estimated to be available in the colon, sigmoid colon and rectum.
Absorption: Mesalazine release from Salofalk granules starts after a lag phase of about 2-3 hrs. Peak plasma concentrations are reached at about 4-5 hrs. The systemic bioavailability of mesalazine after oral administration is estimated to be approximately 15-25%.
Food intake delays absorption by 1-2 hrs but does not change the rate and extent of absorption.
Elimination: From a 3 x 500 mg daily mesalazine dose in long-term therapy, a total renal elimination of mesalazine and N-Ac-5-ASA under steady-state conditions was calculated to be about 25%. The unmetabolized excreted mesalazine part was <1% of the oral dose. The elimination half-life (t_½) in this study was 4.4 hrs.
Toxicology: Preclinical Safety Data: Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity, carcinogenicity (rat) or toxicity to reproduction.
Kidney toxicity (renal papillary necrosis and epithelial damage in the proximal convoluted tubule or the whole nephron) has been seen in repeat-dose toxicity studies with high oral doses of mesalazine. The clinical relevance of this finding is unknown.