A clinical trial on absorption and <i>N</i>‐acetylation of oral and rectal mesalazine

Dilger, Karin; Trenk, Dietmar; Rössle, Martin; Çap, Murat; Zähringer, A.; Wacheck, Volker; Remmler, Cornelia; Cascorbi, Ingolf; Kreisel, Wolfgang; Novacek, Gottfried

doi:10.1111/j.1365-2362.2007.01809.x

Cited by 17 publications

(14 citation statements)

References 34 publications

(72 reference statements)

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“…The pharmacokinetics of the drug include its conversion to N-acetyl 5-ASA as the major metabolite, along with other minor metabolites (2,19,60). Whereas inflammation affects therapeutic outcomes by regulating the expression, activity, and functions of many drug-metabolizing enzymes and drug transporters (45,51,62,65), human studies have produced only conflicting reports of whether colonic inflammation affects 5-ASA metabolism (2,19,36). We therefore tested in mice if acute inflammation affects N-acetylation of 5-ASA, and the expression and function of the NAT enzymes mediating this metabolic conversion.…”

Section: Discussionmentioning

confidence: 99%

“…After 5-ASA administration, the N-acetylation of 5-ASA produces the major metabolite (Ac-5-ASA), which can be detected in colonic tissue, colonic lumen, plasma, and urine along with minor metabolites (2,19,60). 5-ASA is known to act locally in the intestinal mucosa, since its efficacy is more closely correlated to drug mucosal concentration rather than blood concentration (17).…”

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confidence: 99%

“…Unfortunately, this has only been examined in small studies using IBD patients with diverse clinical status, and results are conflicting. It has been reported that IBD patients with active disease have a lowered plasma Ac-5-ASA-to-5-ASA ratio vs. healthy controls (19), but this conflicts with observations of others who saw no change in 5-ASA acetylation rates in colonic biopsy homogenates or isolated colonocytes from IBD patients (2,36,41). At present, we cannot firmly predict if decreased 5-ASA metabolism is a reproducible finding in inflamed tissue or if such a change in metabolism would improve or reduce the clinical benefit of 5-ASA therapy.…”

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confidence: 99%

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Acute murine colitis reduces colonic 5-aminosalicylic acid metabolism by regulation of N-acetyltransferase-2

Ramírez-Alcántara

Montrose

2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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Ramírez-Alcántara V, Montrose MH. Acute murine colitis reduces colonic 5-aminosalicylic acid metabolism by regulation of N-acetyltransferase-2. Am J Physiol Gastrointest Liver Physiol 306: G1002-G1010, 2014. First published April 17, 2014 doi:10.1152/ajpgi.00389.2013.-Pharmacotherapy based on 5-aminosalicylic acid (5-ASA) is a preferred treatment for ulcerative colitis, but variable patient response to this therapy is observed. Inflammation can affect therapeutic outcomes by regulating the expression and activity of drug-metabolizing enzymes; its effect on 5-ASA metabolism by the colonic arylamine N-acetyltransferase (NAT) enzyme isoforms is not firmly established. We examined if inflammation affects the capacity for colonic 5-ASA metabolism and NAT enzyme expression. 5-ASA metabolism by colonic mucosal homogenates was directly measured with a novel fluorimetric rate assay. 5-ASA metabolism reported by the assay was dependent on Ac-CoA, inhibited by alternative NAT substrates (isoniazid, p-aminobenzoylglutamate), and saturable with Km (5-ASA) ϭ 5.8 M. A mouse model of acute dextran sulfate sodium (DSS) colitis caused pronounced inflammation in central and distal colon, and modest inflammation of proximal colon, defined by myeloperoxidase activity and histology. DSS colitis reduced capacity for 5-ASA metabolism in central and distal colon segments by 52 and 51%, respectively. Use of selective substrates of NAT isoforms to inhibit 5-ASA metabolism suggested that mNAT2 mediated 5-ASA metabolism in normal and colitis conditions. Western blot and real-time RT-PCR identified that proximal and distal mucosa had a decreased mNAT2 protein-to-mRNA ratio after DSS. In conclusion, an acute colonic inflammation impairs the expression and function of mNAT2 enzyme, thereby diminishing the capacity for 5-ASA metabolism by colonic mucosa. drug metabolism; fluorescence; dextran sulfate sodium; myeloperoxidase; kinetics; enzymatic assay; inflammatory bowel disease; enzyme isoform THE TWO MAJOR INFLAMMATORY bowel diseases (IBD), ulcerative colitis (UC) and Crohn's disease, afflict 1.4 million individuals in the United States (USA) and 2.2 million in Europe (42). To induce and maintain mucosal healing of the colonic mucosa, the major goal of UC therapy is to reduce or eliminate colonic inflammation. For mild to moderate inflammation, therapy based on the nonsteroidal anti-inflammatory compound 5-aminosalicylic acid (5-ASA) is frequently prescribed. In information compiled by the National Institutes of Health from the 2004 Verispan database of prescriptions filled at retail pharmacies in the USA, 5-ASA or its prodrugs accounted for 44% of Crohn's disease prescriptions and 81% of UC prescriptions (23). It is not well understood how 5-ASA induces its antiinflammatory effect on colonic mucosa, but multiple mechanisms have been proposed, including inhibition of intestinal macrophage chemotaxis (47), inhibition of proinflammatory cytokine release (25), inhibition of cyclooxygenase and prostaglandin pathways (28), inhibition of nuclear fa...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Acute murine colitis reduces colonic 5-aminosalicylic acid metabolism by regulation of N-acetyltransferase-2

Ramírez-Alcántara

Montrose

2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Systemic exposure to 5-ASA was shown to be lower after rectal administration than after oral administration of the same dose [28]. This might be due to the physiological absence of specific uptake transporters in intestinal mucosa.…”

Section: Pharmacokinetic and Pharmacodynamic Considerationsmentioning

confidence: 93%

Clinical Pharmacokinetic and Pharmacodynamic Considerations in the Treatment of Ulcerative Colitis

et al. 2018

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“…Also, the reported lack of differences in mesalazine response and tolerability between NAT1 genotypes [9,10] does not exclude differences in mesalazine pharmacokinetics, because differences in activity in NAT1 variants are limited [24,25] and pharmacodynamic parameters are less sensitive than pharmacokinetic parameters. Finally, in patients the degree of intestinal inflammation affects mesalazine pharmacokinetics [26]. Further research is needed to improve our understanding of the fate of mesalazine in the human body in order to assess a rationale for individual dose optimisation, with the chance to improve the risk/benefit ratio of this drug and maybe also to to reduce the risk for rare adverse effects such as interstitial nephritis [27].…”

Section: Discussionmentioning

confidence: 99%

Mesalazine pharmacokinetics and NAT2 phenotype

Lück

Kinzig

Jetter

et al. 2008

Eur J Clin Pharmacol

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BACKGROUND: Mesalazine undergoes extensive metabolism by N-acetylation. While there is some evidence for an involvement of N-acetyltransferase (NAT) type 1, a potential role of NAT type 2 (NAT2) in vivo has not been tested. METHODS: In two studies in healthy young Caucasians, NAT2 phenotyping was carried out using a caffeine metabolic ratio in urine 4-6 h postdose. In study A, 1,000 mg mesalazine doses were given thrice daily for 5 days, and urine and blood samples were drawn during the last dosing interval. In study B, a 1,000 mg single dose was given, and samples were taken for 48 h postdose. Pharmacokinetics of mesalazine and N-acetylmesalazine (LC-MS/MS) were calculated by noncompartmental methods. RESULTS: NAT2 phenotype could be allocated unequivocally in 21 slow and 5 rapid acetylators in study A, and in 9 slow and 8 rapid acetylators in study B. Geometric mean (CV%) values in study A for slow [rapid] acetylators were as follows: mesalazine AUC 11.1 microg/mL.h (51%) [12.0 microg/mL.h (52%)], N-acetylmesalazine AUC 27.7 microg/mL.h (32%) [30.5 microg/mL.h (27%)], mesalazine Ae 8.53% (89%) Statistics provided no evidence for a true difference in mesalazine pharmacokinetics between slow and rapid acetylators, and no significant correlation between NAT2 activity and any mesalazine pharmacokinetic parameter was found. CONCLUSION: NAT2 has no major role in human metabolism of mesalazine in vivo.

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A clinical trial on absorption and N‐acetylation of oral and rectal mesalazine

Abstract: Rectal delivery of 5-ASA results in low systemic drug exposure with potentially reduced toxicity in comparison with oral drug administration. Chronic inflammation of colorectal mucosa might be a relevant source of variability in pharmacokinetics of 5-ASA.

Cited by 17 publications

References 34 publications

Acute murine colitis reduces colonic 5-aminosalicylic acid metabolism by regulation of N-acetyltransferase-2

Acute murine colitis reduces colonic 5-aminosalicylic acid metabolism by regulation of N-acetyltransferase-2

Clinical Pharmacokinetic and Pharmacodynamic Considerations in the Treatment of Ulcerative Colitis

Mesalazine pharmacokinetics and NAT2 phenotype

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