Is N‐acetylation of 5‐aminosalicylic acid reversible in man?

Meese, Claus O.; Fischer, Christine; Klotz, Ulrich

doi:10.1111/j.1365-2125.1984.tb02513.x

Cited by 21 publications

(4 citation statements)

References 14 publications

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“…However, our studies with the direct administration of Ac-5-ASA labelled with the stable isotope deuterium have proven that N-acetylation of 5-ASA is not reversible in rats (Fischer et al, 1984) or humans· (Meese et al, 1984). In healthy subjects renal clearance ranged between 200 and 300 ml/min and the elimination half-life varied between 6 and 9 hours (Meese et al, 1984). In healthy subjects renal clearance ranged between 200 and 300 ml/min and the elimination half-life varied between 6 and 9 hours (Meese et al, 1984).…”

Section: Elimination Kinetics Ofmentioning

confidence: 76%

Clinical Pharmacokinetics of Sulphasalazine, Its Metabolites and Other Prodrugs of 5-Aminosalicylic Acid

Klotz

1985

Clinical Pharmacokinetics

247

110

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There is accumulating clinical evidence that 5-aminosalicylic acid (5-ASA) represents the therapeutic moiety of sulphasalazine in the treatment of inflammatory bowel disease. For more than 4 decades, the active metabolite, 5-ASA, has been administered in the form of the 'prodrug' sulphasalazine; however, in contrast to sulphasalazine, the pharmacokinetics of 5-ASA were unknown until recently. Sulphasalazine itself is poorly absorbed (3 to 12%) and its elimination half-life of about 5 to 10 hours is probably affected by the absorption process. The major part of sulphasalazine is split by bacterial azo-reduction in the colon into 5-ASA and sulphapyridine, the latter accounting for most of the adverse effects of sulphasalazine. The effective cleavage of sulphasalazine depends on an intact colon and transit time. It is markedly reduced in patients taking antibiotics and after removal of the large bowel. The formed sulphapyridine is almost completely absorbed and eliminated by hydroxylation, glucuronidation and polymorphic acetylation. Depending on the genetic phenotype, the elimination half-life and apparent oral clearance of sulphapyridine are approximately 14 hours and 40 ml/min (slow acetylators) or 6 hours and 150 ml/min (fast acetylators), respectively. Of the 5-ASA released from its 'vehicle' sulphapyridine in the colon, at least 25% is absorbed and after acetylation is subsequently excreted in the urine. At least 50% is eliminated in the faeces. Recently, 5-ASA has also been administered directly in the form of enemas, suppositories and oral slow-release preparations. While the elimination half-life of 5-ASA is short (0.5 to 1.5 h), its major acetylated metabolite (which may be active) exhibits a half-life of 5 to 10 hours. During therapy with sulphasalazine or 5-ASA, steady-state plasma concentrations of 5-ASA are relatively low (less than or equal to 2 micrograms/ml); thus its mode of action appears to be topically rather than systemically. Another approach to deliver the active 5-ASA to the gastrointestinal tract is accomplished with novel 'prodrugs' of 5-ASA, in which the carrier molecule sulphapyridine is replaced by 5-ASA itself (azodisalicylate) or other compounds.

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Section: Elimination Kinetics Ofmentioning

confidence: 76%

Clinical Pharmacokinetics of Sulphasalazine, Its Metabolites and Other Prodrugs of 5-Aminosalicylic Acid

Klotz

1985

Clinical Pharmacokinetics

247

110

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“…'0 There is certainly no suggestion that 5-ASA is formed from the administered Ac-ASA, as no 5-ASA is detected in the urine or faeces after administration of Ac-ASA,9 and in two volunteers, when deuterated Ac-ASA was administered rectally, there was no de-acetylation and re-acetylation noted. 16 In this study, we have used the isolated human colonic epithelial cell as a means of comparing the uptake of Ac-ASA with that of 5-ASA. The colonic epithelial cell is probably the major site of acetylation of 5-ASA when the drug is delivered in an appropriate way to the colon,4 and as the N-acetyltransferase enzyme is cytosolic, 5-ASA must be taken up by the epithelial cell before acetylation can take place.…”

Section: Discussionmentioning

confidence: 99%

Comparison of 5-aminosalicylic acid and N-acetylaminosalicylic acid uptake by the isolated human colonic epithelial cell.

Ireland

Priddle

Jewell

1992

Gut

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Isolated human colonic epithelial cell suspensions were incubated with either 0.1 mM 5-aminosalicylic acid (5-ASA) or 0.1 mM acetylaminosalicylic acid (Ac-ASA) for up to two hours. Intra-and extracellular 5-ASA and Ac-ASA were measured by high performance liquid chromatography. Mean 5-ASA uptake in one hour was 160-5 nmollg dry weight, compared with an Ac-ASA uptake of only 5.75 nmollg dry weight. No unchanged 5-ASA was detected inside the cell. Repeated washing had no effect on the intracellular Ac-ASA concentration. This discrepancy in drug uptake may explain why Ac-ASA seems to be ineffective when given to patients with ulcerative colitis. (Gut 1992; 33: 1343-1347 5-Aminosalicylic acid (5-ASA) is the active ingredient of sulphasalazine in ulcerative colitis,' and is thought to work by a local mechanism. The absorption of 5-ASA by the colon is poor, resulting in very low serum and urine concentrations2 and high faecal concentrations.3 The main metabolite of 5-ASA is N-acetyl ASA (Ac-ASA), and the drug is found predominantly in this form in the body. The site of acetylation of 5-ASA was widely assumed to be the liver, but it has recently been shown that the human colonic epithelial cell is capable of acetylating 5-ASA, and that N-acetyltransferase activity is present in the cytosol.4 In addition, it has been shown that Ac-ASA is the form of the drug predominantly found in the rectal mucosa of patients taking oral sulphasalazine.5It has been suggested that this acetylation process may inactivate the drug, and the results of clinical treatment trials of Ac-ASA have been conflicting,'-with the drug being ineffective in two out of three trials. One possible explanation for this discrepancy might be that Ac-ASA is less well taken up by the colonic mucosa, and there is indirect evidence to suggest that this so.' 1" The aim of this study was to compare the uptake of 5-ASA with that of Ac-ASA into the isolated human colonic epithelial cell. Aliquots (2 ml) ofcell suspension were incubated, in duplicate or triplicate, with 01 mM 5-ASA and 5 mM glucose for one hour at 37°C in a shaking water bath (at 70-80 oscillations/ minute). The incubation was terminated by rapid centrifugation, following which the supernatant was analysed for the presence of Ac-ASA by high performance liquid chromatography (HPLC). Intracellular 5-ASA and Ac-ASA were measured by resuspending the cell pellet in 1 ml 0.05 M phosphate buffer, and disrupting it ultrasonically by six, 5 second bursts using an ultrasonicator (MSE). Control experiments were performed to assess the ability of the KrebsHenseleit saline, and also the supernatant of a cell suspension, to acetylate 5-ASA. It has previously been shown that there is no acetyltransferase enzyme activity in the epithelial cell membrane.4 The intracellular and extracellular production of Ac-ASA was therefore deemed to be the result of 5-ASA uptake and subsequent metabolism -that is, equivalent to 5-ASA uptake.

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“…Il processo metabolico è saturabile e irreversibile, ma non risente del polimorfismo genetico dell'enzima [25,[27][28][29].…”

Section: Metabolismounclassified

“…L'emivita di eliminazione del metabolita Nacetil-5-ASA è invece di circa 6 ore. Tali valori sono simili dopo somministrazione orale o rettale [25,27].…”

Section: Emivita E Clearanceunclassified

Mesalazina: profilo farmacologico, terapeutico e farmacoeconomico

Eandi

Ferrero

2003

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NTRODUZIONELa malattia di Crohn e la colite ulcerosa, chiamate anche malattie infiammatorie croniche dell'intestino (IBD, da Inflammatory Bowel Disease), sono caratterizzate da disordini intestinali cronici di origine sconosciuta.Negli USA e in Europa l'incidenza della colite ulcerosa e del morbo di Crohn è stimata rispettivamente in circa 7 e 5 casi su 100.000 abitanti [1][2]. Questi valori, tuttavia, variano in relazione a fattori geografici ed ambientali, nonché in relazione a gruppi socioeconomici e alle origine etniche [3].È stato dimostrato un chiaro tratto genetico associato a queste malattie, tuttavia non sono stati chiariti i legami con numerosi fattori ambientali [4]. Entrambe le malattie possono presentarsi ad ogni età, ma più frequentemente nella terza decade di vita. Sebbene siano relativamente rare e raramente fatali, le IBD si presentano tipicamente nel periodo di vita economicamente produttiva dell'uomo, richiedono importanti e lunghe PROFILO ABSTRACTThe term inflammatory bowel diseases (IBD) refers to two distinct clinical entities: Crohn's disease and ulcerative cholitis, two chronic and non-specific disorders of unknown origin. Although quite uncommon and usually not life-threatening, IBDs have a strong economical impact, as they tend to affect patients in high productivity ages and require long and demanding therapies, medical and sometimes surgical. The pharmacological approaches to IBD treatment include aminosalicylates, corticosteroids and immunosuppressive agents. Aminosalicylic acids are the most widely used agents for maintaining remission and for the cure of mild-tomoderate forms of IBDs. This paper outlines the main pharmacological and clinical properties of one of these drugs, mesalamine (mesalazine). Mesalamine is the active moiety of sulfasalazine, an effective but not always tolerated agent. Mesalamine is available in several pharmaceutical forms, to be administered either by the oral or by the rectal route. As the therapeutic action of aminosalicylates is ascribed to their topical action on the inflamed intestine, while the adverse effects are believed to be caused by the systemically adsorbed (mainly in the first tract of the small bowel) fraction, slow-release formulations are usually preferred. From an economical point of view, mesalamine appears to have a moderate acquisition cost, widely offset by the savings induced on direct sanitary and, most importantly, indirect costs of IBDs. In particular, the availability of a generic drug with advanced colon-delivery technology provides the physician with the opportunity to treat patients with the best available technology at a reasonable price. Farmeconomia e percorsi terapeutici 2003; 4 (4): 201-216cure mediche, e in alcuni casi chirurgiche, e sono complessivamente un rilevante onere economico per il Sistema Sanitario Nazionale (SSN) e per la società [5].Gli approcci terapeutici alle IBD dipendono dall'estensione, dalle localizzazioni e dalla gravità della malattia, essi includono il trattamento con aminosalicilati, corticosteroid...

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Is N‐acetylation of 5‐aminosalicylic acid reversible in man?

Cited by 21 publications

References 14 publications

Clinical Pharmacokinetics of Sulphasalazine, Its Metabolites and Other Prodrugs of 5-Aminosalicylic Acid

Clinical Pharmacokinetics of Sulphasalazine, Its Metabolites and Other Prodrugs of 5-Aminosalicylic Acid

Comparison of 5-aminosalicylic acid and N-acetylaminosalicylic acid uptake by the isolated human colonic epithelial cell.

Mesalazina: profilo farmacologico, terapeutico e farmacoeconomico

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