Chemical formula: C₇H₇NO₃ Molecular mass: 153.135 g/mol PubChem compound: 4075
Mesalazine is an aminosalicylate. The mechanism of action of mesalazine is not fully understood, but appears to have a topical anti-inflammatory effect on the colonic epithelial cells. Mucosal production of arachidonic acid metabolites, both through the cyclooxygenase and lipoxygenase pathways, is increased in patients with chronic inflammatory bowel disease, and it is possible that mesalazine diminishes inflammation by blocking cyclooxygenase and inhibiting prostaglandin production in the colon. Mesalazine has the potential to inhibit the activation of nuclear factor kappa B (NFкB) and consequently the production of key proinflammatory cytokines. More recently, it has been proposed that impairment of PPAR-γ nuclear receptors, (γ-form of the peroxisome proliferator-activated receptors) may be implicated in ulcerative colitis. PPAR-γ receptor agonists have shown efficacy in ulcerative colitis and evidence has been accumulating that the mechanism of action of mesalazine may be mediated by PPAR-γ receptors.
The mesalazine tablet contains a core of mesalazine (5-aminosalicylic acid) 1.2g formulated in a multi-matrix system. This system is coated with methacrylic acid–methyl methacrylate copolymer (1:1) and methacrylic acid–methyl methacrylate copolymer (1:2), which are designed to delay release of mesalazine until exposure to approximately pH 7.
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. 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 mechanism of action of mesalazine (5-ASA) is not fully understood but appears to be topical, and therefore the clinical efficacy of mesalazine does not correlate with the pharmacokinetic profile. A major pathway of clearance of mesalazine is via metabolism to N-acetyl-5-aminosalicylic acid (Ac-5-ASA), which is pharmacologically inactive.
Mesalazine suppositories are designed to provide the distal part of the intestinal tract with high concentrations of mesalazine and a low systemic absorption. They are used to treat the rectum.
Gamma-scintigraphy studies have shown that a single dose of mesalazine 1.2g passed rapidly and intact through the upper gastrointestinal tract of fasted healthy volunteers. Scintigraphic images showed a trail of radio-labelled tracer through the colon, indicating that mesalazine had spread throughout this region of the gastrointestinal tract. Complete disintegration of mesalazine and complete release of mesalazine occurred after approximately 17.4 hours.
The total absorption of mesalazine from mesalazine 2.4g or 4.8g given once daily for 14 days to healthy volunteers was found to be approximately 21-22% of the administered dose.
In a single dose study, mesalazine 1.2g, 2.4g and 4.8g were administered in the fasted state to healthy subjects. Plasma concentrations of mesalazine were detectable after 2 hours (median) and reached a maximum by 9-12 hours (median) on average for the doses studied. The pharmacokinetic parameters are highly variable among subjects. Mesalazine systemic exposure in terms of area under the plasma concentration-time curve (AUC) was dose proportional between 1.2g and 4.8g mesalazine. Maximum plasma concentrations (Cmax) of mesalazine increased approximately dose proportionately between 1.2g and 2.4g and less than dose proportional between 2.4g and 4.8g mesalazine, with the dose normalised value at 4.8g representing, on average, 74% of that at 2.4g based on geometric means.
In a single and multiple dose pharmacokinetic study of mesalazine 2.4 and 4.8g administered with standard meals in 56 healthy volunteers plasma concentrations of mesalazine were detectable after 4 hours and were maximal by 8 hours after the single dose. At steady state (achieved generally by 2 days after dosing), 5-ASA accumulation was 1.1- to 1.4- fold for the 2.4g and 4.8g dose, respectively, above that expected on the basis of single dose pharmacokinetics.
Administration of a single dose of mesalazine 4.8g with a high fat meal resulted in further delay in absorption and mesalazine plasma levels were detectable after approximately 4 hours following dosing. However, a high fat meal increased systemic exposure of mesalazine (mean Cmax by 91%; mean AUC 16%) compared to results in the fasted state. mesalazine was administered with food in the Phase 3 trials.
In a single dose pharmacokinetic study of mesalazine, 4.8g was administered in the fasted state to 71 healthy male and female volunteers (28 young (18-35yrs); 28 elderly (65-75yrs); 15 elderly (>75yrs)). Increased age resulted in increased systemic exposure (up to approximately 2-fold, based on AUC0-t, AUC0-∞ and Cmax) to mesalazine and its metabolite N-acetyl-5-aminosalicylic acid but did not affect the percentage of mesalazine absorbed. Increased age resulted in a slower apparent elimination of mesalazine, though there was high between-subject variability. Systemic exposures in individual subjects were inversely correlated with renal function as assessed by estimated creatinine clearance.
The absorption following rectal administration is low, but depends on the dose, the formulation and the extent of spread. Based on urine recoveries in healthy volunteers under steady-state conditions given a daily dose of 2g (1g x 2), approximately 10% of the dose is absorbed after administration of suppositories.
Following dosing of mesalazine the distribution profile of mesalazine is presumed to be the same as that of other mesalazine containing products. Mesalazine has a relatively small volume of distribution of approximately 18L confirming minimal extravascular penetration of systemically available drug. Mesalazine is 43% bound and N-acetyl-5-aminosalicylic 78-83% bound to plasma proteins when in vitro plasma concentrations are up to 2.5μg/mL and up to 10μg/mL respectively.
The only major metabolite of mesalazine is N-acetyl-5-aminosalicylic acid, which is pharmacologically inactive. Its formation is brought about by N-acetyltransferase-1 (NAT-1) activity in the liver and in the cytosol of intestinal mucosal cells.
Mesalazine is metabolised both pre-systemically by the intestinal mucosa and systemically in the liver to N-acetyl mesalazine (acetyl mesalazine). The acetylation seems to be independent of the acetylator phenotype of the patient. Some acetylation also occurs through the action of colonic bacteria.
Acetyl mesalazine is thought to be clinically as well as toxicologically inactive, although this remains to be confirmed.
Elimination of absorbed mesalazine is mainly via the renal route following metabolism to N-acetyl-5-aminosalicylic acid (acetylation). However, there is also limited excretion of the parent drug in urine. Of the approximately 21-22% of the dose absorbed, less than 8% of the dose was excreted unchanged in the urine at steady state after 24 hours, compared with greater than 13% for N-acetyl-5-aminosalicylic acid. The apparent terminal half-lives for mesalazine and its major metabolite after administration of mesalazine 2.4g and 4.8g were, on average, 7-9 hours and 8-12 hours, respectively.
There are no data in patients with hepatic impairment taking mesalazine. Systemic exposure to mesalazine increased by up to 2-fold in elderly subjects (>65 years, with a mean creatinine clearance of 68–76 ml/min) compared with younger adult subjects (18-35 years, mean creatinine clearance 124 ml/min) after a 4.8g single dose of mesalazine.
Systemic exposures in individual subjects were inversely correlated with renal function as assessed by estimated creatinine clearance.
The potential impact on the safe use of mesalazine in the elderly population in clinical practice should be considered. Furthermore, in patients with renal impairment, the resultant decrease in the rate of elimination and increased systemic concentration of mesalazine may constitute an increased risk of nephrotoxic adverse reactions.
In different clinical studies with mesalazine, mesalazine plasma AUC in females appeared up to 2-fold higher than in males.
Based on limited pharmacokinetic data, 5-ASA and Ac-5-ASA pharmacokinetics appear comparable between Caucasian and Hispanic subjects.
Pharmacokinetics data have not been investigated in elderly people.
Effects in nonclinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.
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