Pharmacokinetics and safety of single and multiple doses of Asacol tablets in Japanese healthy volunteers.
ABSTRACT The pharmacokinetics and safety of Asacol (Tillotts Pharma AG, Ziefen, Switzerland), which has been used worldwide to treat ulcerative colitis and Crohn's disease, were studied in Japanese healthy male volunteers.
Drug plasma concentrations and urinary and fecal excretions after a single dose (400-4800 mg) and multiple doses (3600 mg/day for 7 days) were investigated.
All adverse events were "not serious." The peak plasma concentration (C max) was reached at 12.3-18.0 hours after a single dose, and the C max and area under the plasma concentration-time curve (AUC) of mesalazine and its N-acetyl metabolite were proportional to the doses. The C max and AUC in non-Japanese subjects reported in the literature were closely correlated to findings in Japanese subjects, and external excretions were also similar in the Japanese and non-Japanese subjects.
Asacol was safe and well tolerated in this Japanese population, and the non-Japanese clinical data could be extrapolated to the Japanese population.
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ABSTRACT: The treatment of ulcerative colitis (UC) with 5-aminosalicylic acid (5-ASA) does not have the same therapeutic effect in all patients. We tested the hypothesis that the effectiveness of the drug is related to its mucosal concentration. Twenty one UC patients receiving oral 5-ASA (2.4-3.2 g/day) were enrolled in the study. Four were also receiving topical treatment (2 g/day). Six endoscopic biopsies were taken from the rectum for measurement of 5-ASA concentrations (ng/mg) by HPLC; soluble interleukin 2 receptor (sIL-2R) concentrations (U/ml) were measured by ELISA and histology. Endoscopic and histological appearance was graded on a four point scale (0-3). The Wilcoxon's rank test and Pearson's correlation coefficient were used for statistical analysis. Mucosal concentrations of 5-ASA were significantly higher (p=0.03) in patients with endoscopic scores of 0-1 compared with those with scores of 2-3 (16.1 (range 10.2-45) v 5. 5 (3.5-17.4), respectively) and in patients with lower histological inflammation compared with those with more severe scores (17.4 (10. 5-45) v 8.9 (3.5-17.2), respectively) (p<0.01). In contrast, mucosal sIL2-R concentrations were significantly lower in patients with slight endoscopic and histological lesions than in those with more severe disease. A significative inverse correlation (r=-0.85) was found between 5-ASA and sIL-2R mucosal concentrations (p=0.00008). In patients with UC, in the same area of the intestinal tract, we found that the higher the 5-ASA mucosal concentrations, the lower the IL-2R levels and endoscopic and histological scores. We hypothesise that maintenance of high mucosal 5-ASA concentrations in all colonic segments could contribute to improve clinical outcome in UC patients.Gut 09/2000; 47(3):410-4. · 10.73 Impact Factor
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ABSTRACT: To compare the disposition of 5-aminosalicylic acid (5-ASA) and its acetylated metabolite during treatment with olsalazine and mesalazine, 14 patients with inactive ulcerative colitis were randomly assigned to olsalazine (1 g twice daily) and the mesalazines, Asacol (800 + 400 + 800 mg daily), Pentasa (750 + 500 + 750 mg daily), and Salofalk (750 + 500 + 750 mg daily) in a crossover design trial so that all received each drug for seven days. Intraluminal colonic concentrations of 5-ASA were estimated after five days by the method of equilibrium in vivo dialysis of faeces. A predose serum sample and a 24 hour urine collection were obtained on day seven. The 5-ASA and acetyl-5-aminosalicylic acid (Ac-5-ASA) values were determined by high performance liquid chromatography. Olsalazine almost doubled the colonic concentrations (mean 23.7 (SEM) (1.9) mmol/l) of its therapeutically active ingredient (5-ASA) compared with equimolar doses of Pentasa (12.6 (2.2) mmol/l; p less than 0.0003) and Salofalk (15.0 (2.0) mmol/l; p less than 0.003). At the same time, olsalazine treatment was associated with lower serum concentrations and urinary excretions (p less than 0.05) of 5-ASA and Ac-5-ASA compared with the mesalazine preparations. The low systemic load of 5-ASA provided by olsalazine reduces the potential risk of nephrotoxicity during long term treatment.Gut 12/1990; 31(11):1271-6. · 10.73 Impact Factor
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ABSTRACT: Existing pharmacokinetic data are insufficient to determine whether a delayed-release formulation of mesalamine (Asacol) results in greater systemic exposure to 5-aminosalicylic acid and its major metabolite N-acetyl-5-aminosalicylic acid than a prodrug (balsalazide). To determine the pharmacokinetic parameters of 5-aminosalicylic acid and N-acetyl-5-aminosalicylic acid from equimolar doses of 5-aminosalicylic acid administered as Asacol and balsalazide. Nineteen healthy volunteers completed an open-label, single-dose, randomized, crossover study comparing the pharmacokinetics of 5-aminosalicylic acid and N-acetyl-5-aminosalicylic acid from equimolar doses of 5-aminosalicylic acid (800 mg) administered as Asacol (800 mg) and balsalazide (2250 mg). Plasma and urine samples were analysed for 5-aminosalicylic acid, N-acetyl-5-aminosalicylic acid, and balsalazide (urine only) using high-performance liquid chromatography methods with mass spectrometric detection. Pharmacokinetic parameters assessed for 5-aminosalicylic acid and N-acetyl-5-aminosalicylic acid included: percentage of dose excreted in urine (A(e)%), area under the plasma concentration-time curve (AUCt(last)); and maximum plasma concentration (C(max)). The geometric mean total (5-aminosalicylic acid and N-acetyl-5-aminosalicylic acid) urinary excretion values (A(e)%) of Asacol and balsalazide were 19.26 and 19.31% (P = 0.98). The geometric mean A(e)% values of 5-aminosalicylic acid for Asacol and balsalazide were 0.39 and 0.37% (P = 0.78); the geometric mean A(e)% values of N-acetyl-5-aminosalicylic acid for Asacol and balsalazide were 18.78 and 18.83% (P = 0.98). The geometric mean 5-aminosalicylic acid AUC(t(last)) values for Asacol and balsalazide were 3295 and 3449 ng h/mL (P = 0.85); the geometric mean N-acetyl-5-aminosalicylic acid AUC(t(last)) values for Asacol and balsalazide were 15 364 and 16 050 ng h/mL (P = 0.69). The geometric mean 5-5-aminosalicylic acid C(max) values for Asacol and balsalazide were 319 and 348 ng/mL (P = 0.80); the geometric mean N-acetyl-5-aminosalicylic acid C(max) values for Asacol and balsalazide 927 and 1009 ng/mL (P = 0.67). The systemic absorption of 5-aminosalicylic acid and N-acetyl-5-aminosalicylic acid from Asacol and balsalazide are comparable based upon plasma pharmacokinetic parameters and urinary excretion values.Alimentary Pharmacology & Therapeutics 06/2004; 19(10):1089-98. · 4.55 Impact Factor