Salofalk Mechanism of Action

Pharmacotherapeutic Group: Granules: Intestinal anti-inflammatory agents; Aminosalicylic acid and similar agents.
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.
Pharmacodynamic effects: 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 realise this, Salofalk granules are gastric juice resistant and release mesalazine in a pH dependent manner, due to Eudragit L coating, and prolonged manner, due to the matrix granule structure.
Pharmacokinetics: Tablet: General aspects 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.
Specific aspects of Salofalk 500 mg: 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 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%.
Granules: General considerations of mesalazine: Absorption: Mesalazine absorption is highest in proximal and lowest in distal gut areas.
Biotransformation: Mesalazine is metabolised both pre-systemically 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%, depending on the 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 the total orally administered mesalazine dose is excreted into the breast milk mainly as N-Ac-5-ASA.
Salofalk Granules specific: Distribution: Owing to the granule size of approx. 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 approx. 3 hours and the ascending colon within approx. 4 hours. The total transit time in the colon amounts to about 20 hours.
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 hours. Peak plasma concentrations are reached at about 4-5 hours. The systemic bioavailability of mesalazine after oral administration is estimated to be approximately 15-25%.
Food intake delays absorption by 1 to 2 hours 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 unmetabolised excreted mesalazine part was less than 1% of the oral dose. The terminal elimination half-life observed after single dose administration of 3 * 500 mg or 3 * 1000 mg Salofalk granules was 10.5 hours.
Toxicology: Preclinical safety data: Granules: 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.