Nonadherence in inflammatory bowel disease: results of factor analysis.

BACKGROUND: The purpose of the study was to assess overall nonadherence to treatment among patients with Crohn's disease (CD) and ulcerative colitis (UC) in a single tertiary center. METHODS: A total of 177 patients were enrolled in this study (84 males, 93 females; 117 CD, 60 UC). Patients were interviewed about their nonadherent behavior and their answers were analyzed using factor analysis. Urine samples were collected from a subcohort of 47 patients treated by mesalamine to verify the presence of 5-ASA or its metabolites. RESULTS: Overall intentional nonadherence was reported by 38.9% of patients; 18.6% of the patients discontinued the treatment at least once. Intentional dose reduction was reported by 18% of patients; 14.7% of patients occasionally did not refill their medications on time. There were no differences in adherence between males and females, disease type, previous bowel surgery, or marital, smoking, and nonsmoking status. More than 38% of patients reported unintentional nonadherence. Factor analysis proved that nonadherence increased with a higher education level of the patients and decreased with older age. Adverse drug effects strongly contributed to nonadherence. Nonadherent patients were more likely to be chronically active or in relapse (tau = 0.212; P = 0.002). In the group of 47 patients whose urine was analyzed, 6 cases (12.7%) were negative for mesalamine or its metabolite. CONCLUSIONS: The overall intentional nonadherence with medical therapy is relatively high among IBD patients and should be taken into account when a patient's response to treatment is unsatisfactory. Therefore, problems of nonadherence should be discussed with all IBD patients.

Studies of compliance with delayed-release mesalazine therapy in patients with inflammatory bowel disease.

BACKGROUND: Non-compliance with maintenance mesalazine therapy may be a risk factor for relapse in inflammatory bowel disease, but the prevalence and determinants of non-compliance are unknown. AIM: To study the prevalence and determinants of non-compliance in patients with inflammatory bowel disease. METHODS: Out-patients receiving delayed-release mesalazine were studied. Compliance was determined by direct enquiry and by analysis of urine samples for 5-aminosalicylic acid/N-acetyl-5-aminosalicylic acid. Potential determinants of compliance were assessed. RESULTS: Ninety-eight patients were studied. Forty-two patients (43%) reported taking <80% of their prescribed dose. Logistic regression revealed the independent predictors of non-compliance to be three-times daily dosing [odds ratio (OR), 3.1; 95% confidence interval (CI), 1.8-8.4] and full-time employment (OR, 2.7; 95% CI, 1.1-6.9). Urine from 12 patients (12%) contained no detectable 5-aminosalicylic acid/N-acetyl-5-aminosalicylic acid, and 18 patients (18%) had levels below those expected. Depression was the only independent predictor of complete non-compliance (OR, 10.5; 95% CI, 1.8-79.0), and three-times daily dosing was the only independent predictor of partial non-compliance (OR, 3.7; 95% CI, 1.8-8.9). Self-reporting correctly identified 66% of patients judged to be non-compliant on urinary drug measurement. CONCLUSIONS: Non-compliance with maintenance mesalazine therapy is common in patients with inflammatory bowel disease. Three-times daily dosing and full-time employment are predictors of partial non-compliance, whilst depression is associated with complete non-compliance. Self-reporting detects most non-compliant patients.

Intrarectal administration of 5-aminosalicylic acid to rabbits and dogs.

Intrarectal administration of 5-aminosalicylic acid (5-ASA) to rabbits and dogs was performed to obtain safety data. Groups of rabbits and dogs received twice daily intrarectal doses of 250, 500 or 1000 mg 5-ASA for 14 consecutive days. Treatment had no adverse effect on the behaviour or performance of the animals and microscopic examination revealed no evidence of systemic or local toxicity.

Synthesis and in vitro/in vivo evaluation of 5-aminosalicyl-glycine as a colon-specific prodrug of 5-aminosalicylic acid.

A simple synthetic route for the preparation of amino acid conjugate of 5-aminosalicylic acid (5-ASA) was exploited and prepared 5-aminosalicyl-glycine (5-ASA-Gly) in good yield. In vitro and in vivo properties of 5-ASA-Gly as a colon-specific prodrug of 5-ASA were investigated using rats as the test animal. Incubation of 5-ASA-Gly with cecal or colonic contents at 37 degrees C released 5-ASA in 65 or 27% of the dose in 8 h, respectively. No 5-ASA was detected from the incubation of 5-ASA-Gly with the homogenates of stomach or small intestine. Plasma concentration of 5-ASA-Gly decreased rapidly after intravenous administration of 5-ASA-Gly, and no 5-ASA was detected in the blood, which indicated 5-ASA-Gly was not degraded in the plasma. After oral administration of 5-ASA-Gly, about 50% of the administered dose was recovered as 5-ASA and N-acetyl-ASA and 3% as 5-ASA-Gly from feces and 14% as 5-ASA-Gly and 28% as 5-ASA and N-acetyl-ASA from urine in 24 h. These results suggested that a large fraction of 5-ASA-Gly was delivered to the large intestine and activated to liberate 5-ASA. For comparison, total recovery of 5-ASA and N-acetyl-5-ASA from feces after oral administration of 5-ASA-Gly was greater than that from sulfasalazine, which is one of the most commonly prescribed prodrugs of 5-ASA.

Systemic levels of free 5-aminosalicylic acid depend on the nature of the 5-aminosalicyclic acid derivative and not on disease activity or extent in patients with inflammatory bowel disease.

INTRODUCTION: Several new derivatives of sulphasalazine that make use of its active moiety, 5-aminosalicylic acid (5-ASA), have been introduced for the treatment of inflammatory bowel disease (IBD). In rats short term intravenous administration of 5-ASA has been associated with nephrotoxicity. A number of cases of nephrotoxicity have been reported recently in IBD patients taking oral maintenance treatment with 5-ASA compounds. OBJECTIVE: To study the urinary and serum levels of acetylated 5-ASA (Ac-5-ASA) and the unacetylated 5-ASA (5-ASA) in patients with IBD maintained on sulphasalazine, olsalazine and mesalazine (pH dependent release form). We also sought correlation between levels of 5-ASA, clinical disease activity and extent of disease. METHODS: We studied 79 patients (male, n = 30; female, n = 49) with established IBD [ulcerative colitis (UC), n = 48; Crohn's disease (CD), n = 31], 72 maintained on 5-ASA compounds (sulphasalazine = 27; olsalazine = 28; mesalazine = 17) and 7 patients were receiving no medication. Urinary and serum analysis of 5-ASA was performed by high performance liquid chromatography (HPLC). Clinical disease activity was quantified using simple index of Harvey and Bradshaw. RESULTS: Patients receiving mesalazine had significantly higher levels of serum free 5-ASA compared to those who were receiving olsalazine and sulphasalazine (mesalazine mean +/- SEM; range; 2.84 +/- 1.21 (0.00-16.00) vs olsalazine 0.45 +/- 0.18 (0.00-16.20); mumol/L; p < 0.04; sulphasalazine 0.37 +/- 0.25 (0.00-3.74); p < 0.03). Similarly levels of urinary free 5-ASA were significantly higher in patients maintained on mesalazine compared to those on olsalazine or sulphasalazine (mesalazine 219 +/- 80.43 (0.00-1050) vs olsalazine 33.3 +/- 17.23 (0.00-317) mumol/L; p < 0.01; and sulphasalazine 15 +/- 8.86 (0.00-192); p < 0.05). However, no significant difference was observed in the levels of urinary free 5-ASA between olsalazine and sulphasalazine. No significant difference was observed in the levels of free-5-ASA in UC patients with left sided disease and those with extensive disease. Furthermore, no significant difference was observed in the levels of serum and urinary 5-ASA in CD patients with ileo-colic disease and colonic disease. Urinary and serum free-5-ASA did not correlate with the clinical disease activity. CONCLUSION: Systemic absorption of 5-ASA from sulphasalazine and olsalazine is relatively low. However, pH-dependent mesalazine formulations may release their contents rapidly in the small intestine and proximal colon resulting in higher plasma and urinary concentrations of free 5-ASA. The effects of free 5-ASA on renal function in the human require further evaluation.

Simple method for the determination of 5-aminosalicylic and N-acetyl-5-aminosalicylic acid in rectal tissue biopsies.

We describe a sensitive high-performance liquid chromatographic method for the determination of 5-aminosalicylic acid and N-acetyl-5-aminosalicylic acid in rectal tissue biopsies. Samples were derivatised using propionic anhydride and proteins were precipitated with methanol. A Supelcosil ABZ column (150x4.6 mm I.D., 5 microm silica particles) was used with a mobile phase comprising 0.1 M acetic acid, acetonitrile and triethylamine (1600:114:6, v/v/v). Fluorescence detection was employed and detection limits were 0.2 ng/mg tissue at a signal-to-noise ratio of three (measured concentration: 5-aminosalicylic acid, 0.254 (0.228-0.286) ng/mg, C.V. 10.7%; N-acetyl-5-aminosalicylic acid, 0.18 (0.154-0.198) ng/mg, C.V 9.8%). This assay was validated for use with serum, urine and faecal samples for which it proved to be both precise and accurate (C.V.<10%, measured concentration within 10%).

Determination of p-aminosalicylic acid and its N-acetylated metabolite in human urine by capillary zone electrophoresis as a measure of in vivo N-acetyltransferase 1 activity.

A capillary zone electrophoresis method has been developed for the determination of p-aminosalicylic acid (PAS) and its metabolite, N-acetyl-p-aminosalicylic acid (N-acetyl-PAS), in urine. A linear relationship was observed between time-normalized peak area and the concentration of the parent and metabolite with correlation coefficients greater than 0.9990. The method could be applied to the determination of PAS and N-acetyl-PAS in human urine without any sample pretreatment. A good separation of the analytes is achieved in a run time of 12 min (15 min total, including capillary wash). Using PAS as a probe for N-acetyltransferase 1 activity, 20 healthy volunteers were phenotyped after oral administration of a 1 g dose. The preliminary results seem to indicate a bimodal distribution of N-acetyl-PAS/PAS molar ratios.

Systemic absorption of 5-aminosalicylic acid in patients with inactive ulcerative colitis treated with olsalazine and mesalazine.

OBJECTIVE: To compare the systemic load of 5-aminosalicylic acid (5-ASA) as a basis for potential long-term toxicity during treatment in usual dosage with olsalazine (Dipentum) and one controlled-release mesalazine preparation (Salofalk) in patients with inactive ulcerative colitis. DESIGN: Open, randomized, crossover study. TREATMENT SCHEDULE: Olsalazine 500 mg twice daily for 7 days and mesalazine 500 mg thrice daily for 7 days consecutively. PATIENTS: Fifteen patients (12 males/3 females) aged between 18-70 years with ulcerative colitis in endoscopically confirmed remission for at least one month. METHODS: A morning predose plasma sample and a 24-h urine collection on days 6 and 7 of each course were obtained from all patients for quantitative determination of 5-ASA and acetyl-5-ASA (Ac-5-ASA) concentrations. High performance liquid chromatography was used and all analyses were performed blindly on coded samples. RESULTS: Treatment with mesalazine compared with olsalazine gave significantly higher levels of 5-ASA and Ac-5-ASA in plasma and urine. Maximum values and ranges of all variables were higher in the mesalazine group than in the olsalazine group. It is noteworthy that there was clear discriminance in the range of urine 5-ASA and Ac-5-ASA concentrations after mesalazine and olsalazine treatment. CONCLUSION: 1. The mesalazine preparation used, in comparison with olsalazine given in usual dosages, causes significantly higher levels of 5-ASA and Ac-5-ASA in plasma and urine in patients with inactive ulcerative colitis. 2. The lower systemic load of 5-ASA may reduce the potential risk of adverse events and in particular of nephrotoxicity.

Systemic availability of 5-aminosalicylic acid: comparison of delayed release and an azo-bond preparation.

AIM: To determine the systemic uptake of 5-aminosalicylic acid (5-ASA) and acetyl-5-ASA (Ac-5-ASA) at steady state during treatment with either an azo-bond preparation, olsalazine, or a delayed-release mesalazine. METHODS: In an open cross-over trial with randomized sequence, 15 patients with ulcerative colitis in remission were given 7-day courses of olsalazine (Dipentum 1.0 g daily) and of mesalazine (Asacol 1.6 g daily). Plasma and urine were collected on days 6 and 7 of each course and concentrations of 5-ASA and Ac-5-ASA were determined by high-performance liquid chromatography (HPLC). RESULTS: Mean steady-state plasma concentrations of 5-ASA and Ac-5-ASA were significantly higher after treatment with mesalazine than with olsalazine (P < 0.0001). Total urinary excretion of 5-ASA and Ac-5-ASA as a percentage of the given dose was significantly higher on mesalazine than on olsalazine (P < 0.01). Only two patients experienced, during the first 3 days of treatment with olsalazine, transient watery diarrhoea which resolved spontaneously. No unexpected or major changes in haematology or biochemistry were detected during the study. CONCLUSION: As 5-ASA acts locally, the lower systemic load provided by olsalazine may increase efficacy and reduce the potential risk of nephrotoxicity during long-term maintenance treatment of ulcerative colitis.

Delivery and fate of oral mesalamine microgranules within the human small intestine.

BACKGROUND/AIMS: Oral use of mesalamine in inflammatory bowel disease requires slow-release preparations to prevent premature absorption and inactivation. Resulting luminal concentrations within the human small intestine are unknown. The aim of this study was to determine human intestinal delivery patterns of mesalamine from a microgranule preparation (Pentasa; Ferring Arzeimittel, Kiel, Germany) effective in Crohn's disease with small bowel involvement. METHODS: A multilumen tube for duodenal, jejunal, and ileal aspiration and marker perfusion was placed in 6 normal subjects. Levels of luminal, plasma, and urinary mesalamine and its main metabolite, acetyl mesalamine, were measured for 7 hours after ingestion of mesalamine (500 mg) with a labeled meal. RESULTS: Gastric emptying of mesalamine paralleled the meal, and its release occurred throughout the small intestine (cumulative, 20% of dose). For 4 hours, mean luminal mesalamine and acetyl mesalamine concentrations were 52 and 38 micrograms/mL (duodenum), 59 and 82 micrograms/mL (jejunum), and 64 and 104 micrograms/mL (ileum). Cumulative colonic delivery was 82% (7% dissolved, 75% in microgranules), and urinary excretion was 3.5%. CONCLUSIONS: Although the major part of continuous-release mesalamine is delivered to the colon, large proportions are liberated and available at high concentrations within the small intestinal lumen, thus explaining its therapeutic efficacy in small intestinal Crohn's disease.

Pharmacokinetics of 5-aminosalicylic acid from controlled-release capsules in man.

One gram single dose of Pentasa controlled-release capsules was administered to 24 healthy volunteers under fasting condition. Mean plasma 5-aminosalicylic acid (5-ASA) and acetyl 5-ASA concentrations peaked at 0.53 microgram.ml-1 and 1.33 micrograms.ml-1 from 3 to 4 hours following dosing, respectively. The half-lives of both compounds could not be determined as absorption of 5-ASA was continuous throughout the gastrointestinal tract. An average of 29.4% (CV: 27%) of the dose was excreted in the urine primarily as acetyl 5-ASA. Up to 91.1% of the dose was released from the capsules. Forty percent of the dose (CV: 40%) was eliminated in the feces, with 8.9% of the dose remained as formulation bounded 5-ASA, indicating that controlled-release capsules continue to release drug throughout the GI tract. 5-ASA contributed 46.7% of the salicylates eliminated in the feces and acetyl 5-ASA accounted for the balance. Controlled-release capsules produced three times more total salicylates and 10 times more total and free 5-ASA in the feces than did 5-ASA suspension. Thus, while lower systemic levels of salicylates were absorbed, greater therapeutic quantities of 5-ASA were available in the bowel.

Pharmacokinetic studies of benzalazine.

The pharmacokinetic properties of benzalazine ((2-hydroxy-5-[(4-carboxyphenyl)azo]benzoic acid, CAS 64896-26-0), a new agent for the treatment of ulcerative colitis and Crohn's disease of the large intestine, were investigated. From jejunal loops of rats in situ no noteworthy absorption of benzalazine was observed. All attempts to demonstrate metabolic conversion of benzalazine in mucosal homogenate of the small intestine of rats were without any success. In faecal suspensions, the half-life of the metabolic conversion of benzalazine was determined as 15 min and the formation of the metabolite 5-aminosalicylic acid (5-ASA) was demonstrated qualitatively. 72 h after single oral administration of 300 mg benzalazine/kg b.w. to rats, an average of 71.83% of the administered dose was recovered in urine and faeces. Only a small amount of unmetabolized benzalazine was excreted with urine and faeces (0.75% and 1.47% of the administered dose, respectively). The benzalazine metabolite 5-ASA and the 5-ASA metabolite acetyl-5-aminosalicylic acid (Ac-5-ASA) were excreted mainly with the faeces (29.22% and 20.66% of the administered dose, respectively) and only in small amounts with the urine (2.54% and 11.06% of the administered dose, respectively).

Brush-border-enzyme-mediated intestine-specific drug delivery. Amino acid prodrugs of 5-aminosalicylic acid.

5-Aminosalicylic acid (5-ASA) is the active principle of a number of preparations aimed at the treatment of inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis, but its efficacy is limited by early absorption and metabolism. The possibility to exploit the selective hydrolytic activity of brush border enzymes such as aminopeptidase A and carboxypeptidases was studied by preparing the following four amino acid prodrugs of 5-ASA: 5-(N-L-aspartylamino)-2-salicylic acid, disodium salt (18), 5-(N-L-glutamylamino)-2-salicylic acid, disodium salt (19), [(5-aminosalicyl)-L-prolyl]-L-leucine, sodium salt (25), and [[5-(N-L-glutamylamino)salicyl]-L-prolyl]-L-leucine, disodium salt (28). In these compounds, the peptide bond is selectively split by the intestinal brush border aminopeptidase A (compounds 18, 19, and 28) and carboxypeptidases (compounds 25 and 28).

Oroileal transit of slow release 5-aminosalicylic acid.

The predominant active anti-inflammatory moiety in chronic inflammatory bowel disease is 5-aminosalicylic acid (5-ASA). As unprotected 5-ASA is rapidly absorbed in the upper gastrointestinal tract several slow release preparations have been developed to permit passage of 5-ASA to the lower small bowel and to the colon. To investigate luminal kinetics and extent of the release of 5-ASA intraluminal concentrations and loads of this compound together with that of its main metabolite acetyl-5-aminosalicylic acid (ac-5-ASA) were studied, over 15 hours after giving the slow release preparation Salofalk at a dose of 500 mg orally together with a test meal. Plasma concentrations and urinary excretion were also measured. Six healthy volunteers swallowed an 11 lumen oroileal tube, which allowed marker perfusion, aspiration of luminal content from the duodenum, mid-jejunum, and ileum, and recording of intestinal motility. Emptying of 5-ASA into the duodenum started after emptying of the meal, together with the first phase III of interdigestive motility. Mean luminal concentrations of 5-ASA and ac-5-ASA increased continuously from duodenum (both: 15 to 30 micrograms/ml) to ileum (60 to 110 micrograms/ml and 80 to 150 micrograms/ml respectively) over three hours and decreased over the next three hours. During 10 hours after eating, 30% of the total dose passed the ileum in solution and another 10% were excreted in urine. Thus about 60% reached the colon unreleased from tablets and another 30% were in solution. The ratio of 5-ASA and ac-5-ASA in solution was about 1:1 in the duodenum and 1:1.5 to 1:2 in the more distal small intestine. The data suggest that the large quantities of intraluminal ac-5-ASA are generated in the intestinal mucosa and reach the lumen by back diffusion. The results show that most of the 5-ASA from this slow release preparation is delivered into the colon, which explains its effectiveness in ulcerative colitis. The considerable luminal concentrations already present in the distal ileum might justify therapeutic trials in Crohn's disease.

Identification of oxidation products of 5-aminosalicylic acid in faeces and the study of their formation in vitro.

The formation of three oxidant-derived products of 5-aminosalicylic acid (5-ASA) in vivo was demonstrated in patients with active ulcerative colitis as well as in healthy subjects. The products were isolated from faeces by preparative HPLC and their chemical structures were found to be oxidation products of 5-ASA using 1H-NMR spectroscopy and mass spectrometry. Reactions carried out in vitro between 5-ASA and oxidants suggested to be present in the inflamed bowel verified that the hypochlorite-mediated oxidation of 5-ASA as well as the haemoglobin-catalysed H2O2-dependent oxidation of 5-ASA resulted in the formation of a single oxidation product of 5-ASA. This product was similar to, but not identical to any of the products identified in faeces from patients receiving 5-ASA. Oxygen radical-mediated oxidation of 5-ASA gave several products, different from the products isolated. Finally, it was verified that the products formed in vivo are not formed as a result of autooxidation of 5-ASA either in faeces extract or in pharmaceuticals.

Disposition of mesalazine from mesalazine-delivering drugs in patients with inflammatory bowel disease, with and without diarrhoea.

The disposition of mesalazine from the azo compounds sulphasalazine and olsalazine (Dipentum) and from the slow-release mesalazine drugs Pentasa, Asacol, and Salofalk was studied in 20 patients with inflammatory bowel disease. Ten of them had diarrhoea, and 10 had normal stools. On the last 2 days of a 7-day maintenance treatment with each of the study drugs urine and faeces were collected for determination of mesalazine, acetyl-mesalazine, and unsplit azo compound. In patients with and without diarrhoea the urinary and the faecal excretion of acetyl-mesalazine was lowest during treatment with olsalazine. The proportion of acetyl-mesalazine in faeces was highest during treatment with Pentasa in both groups. The presence of diarrhoea was associated with a decrease in the proportion of acetyl-mesalazine in faeces during treatment with all drugs, not significant only for Pentasa. The proportion of unsplit azo compound in faeces increased in the case of diarrhoea to almost 50%. It is concluded that in patients with inflammatory bowel disease diarrhoea substantially influences the disposition from all these drugs except Pentasa.

A pharmacokinetic study of sulphasalazine and two new formulations of mesalazine.

We have examined the pharmacokinetics of enteric coated sulphasalazine compared with two new formulations of mesalazine. These consisted of microgranules of mesalazine coated with Eudragit S in a concentration of either 20 or 25% dry lacquer substance; these in turn were enclosed in capsules coated with Eudragit L. In-vitro dissolution studies of coated microgranules showed that drug release was pH dependent. Studies in 7 normal volunteers showed median peak concentrations of 5-amino-salicylic acid and N-acetyl-5-amino-salicylic acid occurred at about 6 hours with both microgranular preparations, compared with sulphasalazine at 15 h. The microgranule formulation coated with 20% Eudragit S gave serum levels and overall systemic absorption similar to values with sulphasalazine. This new formulation may be of value for delivering mesalazine and other therapeutic agents to the colon.

High-performance liquid chromatographic assay of 5-aminosalicylic acid (5-ASA) and its metabolites N-beta-D-glucopyranosyl-5-ASA, N-acetyl-5-ASA, N-formyl-5-ASA and N-butyryl-5-ASA in biological fluids.

A fast, highly sensitive high-performance liquid chromatographic method for the simultaneous determination of 5-aminosalicylic acid (5-ASA) and its metabolites N-beta-D-glucopyranosyl-5-ASA, N-formyl-5-ASA, N-acetyl-5-ASA and N-butyryl-5-ASA has been developed using a dynamically modified silica approach on a 40 mm x 4.6 mm I.D. column packed with 3-microns Hypersil. Plasma proteins are precipitated with acetonitrile. After extraction of the acetonitrile into 1,1,1-trichloroethane an undiluted aqueous phase containing the analytes is obtained. The detection limits are in the range 0.002-0.05 microgram/ml in plasma at a signal-to-noise ratio of 3 using fluorescence detection.

Steady-state pharmacokinetics of a new 4-gram 5-aminosalicylic acid retention enema in patients with ulcerative colitis in remission.

The pharmacokinetic profile of a new 4-g 5-aminosalicyclic acid (5-ASA) retention enema, Mesasal, was investigated. Nine patients with ulcerative colitis in remission and one patient with mild disease activity received one enema for seven consecutive nights. They were admitted to hospital for administration of the eighth enema. Plasma concentration and urinary excretion of 5-ASA and acetyl-5-aminosalicyclic acid (Ac-5-ASA) were studied for 45 h and faecal excretion for 24 h after administration of the last enema. The median peak plasma concentration of 5-ASA was 0.92 (range, 0.59-1.87) micrograms/ml at a median of 11 h after administration, and of Ac-5-ASA 1.62 (range, 1.03-4.36) micrograms/ml at a median of 12 h after administration. On average, the plasma concentration of Ac-5-ASA was almost twice that of 5-ASA at each sampling period. At 24 h after administration the median plasma concentration for 5-ASA was 0.12 (range, 0-0.77) micrograms/ml and for Ac-5-ASA 0.36 (range, 0.01-1.6) micrograms/ml. At 45 h after administration low levels of both 5-ASA (less than 0.2 micrograms/ml) and Ac-5-ASA (less than 0.3 microgram/ml) were noted in two patients, low levels of only Ac-5-ASA (less than 0.1 microgram/ml) in two patients, and neither 5-ASA nor Ac-5-ASA in the other six patients. All patients had detectable urinary levels of both 5-ASA and Ac-5-ASA during the first 4 h after administration. Median urinary recovery during 45 h was 12.6% (range, 5.6-22.2%), indicating a low absorption at steady-state conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Disposition of 5-aminosalicylic acid by olsalazine and three mesalazine preparations in patients with ulcerative colitis: comparison of intraluminal colonic concentrations, serum values, and urinary excretion.

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.