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.     

Drug therapy for ulcerative colitis

Ulcerative colitis (UC) is an inflammatory destructive disease of the large intestine occurred usually in the rectum and lower part of the colon as well as the entire colon. Drug therapy is not the only choice for UC treatment and medical management should be as a comprehensive whole.Azulfidine, Asacol, Pentasa, Dipentum, and Rowasa all contain 5-aminosalicylic acid (5-ASA), which is the topical anti-inflammatory ingredient. Pentasa is more commonly used in treating Crohn‘s ileitis because Pentasa capsules release more 5-ASA into the small intestine than Asacol tablets. Pentasa can also be used for treating mild to moderate UC. Rowasa enemas are safe and effective in treating ulcerative proctitis and proctosigmoiditis. The sulfafree 5-ASA agents (Asacol, Pentasa, Dipentum and Rowasa) have fewer side effects than sulfa-containing Azulfidine. In UC patients with moderate to severe disease and in patients who failed to respond to 5-ASA compounds,systemic (oral) corticosteroids should be used. Systemic corticosteroids (prednisone, prednisolone, cortisone, etc.)are potent and fast-acting drugs for treating UC, Crohn‘s ileitis and ileocolitis. Systemic corticosteroids are not effective in maintaining remission in patients with UC.Serious side effects can result from prolonged corticosteroid treatment. To minimize side effects, corticosteroids should be gradually reduced as soon as the disease remission is achieved. In patients with corticosteroid-dependent or unresponsive to corticosteroid treatment, surgery or immunomodulator is considered. Immunomodulators used for treating severe UC include azathioprine/6-MP,methotrexate, and cyclosporine. Integrated traditional Chinese and Western medicine is safe and effective in maintaining remission in patients with UC.     

Oral 5-aminosalicylic acid preparations in treatment of inflammatory bowel disease an update

Therapeutic efficacy of 5-aminosalicylic acid (5-ASA) preparations is reviewed. In the acute treatment of Crohn's disease, Pentasa and Salofalk seem to be more effective than placebo. When it is given in an equimolar 5-ASA regimen, Salofalk appears to be at least as effective as sulfasalazine (SAS) in the treatment of both Crohn's disease and ulcerative colitis. Asacol and SAS are equally effective in maintenance therapy of ulcerative colitis. Dipentum was more efficient than placebo. There was only a low incidence of side effects from oral 5-ASA preparations, but larger-scale trials may be needed for a more accurate profile of adverse reactions.     

Disposition of 5-aminosalicylic acid from 5-aminosalicylic acid-delivering drugs during accelerated intestinal transit in healthy volunteers

In eight healthy volunteers accelerated intestinal transit time was induced with bisacodyl, and urinary and faecal excretion of sulphasalazine, olsalazine, 5-aminosalicylic acid (5-ASA), and acetyl-5-ASA was studied after a single oral dose of 3.3 mmol sulphasalazine, olsalazine, Pentasa, and Salofalk and 2.6 mmol of Asacol. The faecal and urinary excretion of acetyl-5-ASA was lowest after intake of sulphasalazine and olsalazine and highest after intake of Pentasa and Salofalk. The figures for Asacol were intermediate. This indicates insufficient release of 5-ASA from sulphasalazine and olsalazine. When the results of this study are compared with those of a previous study without accelerated transit time, the disposition of 5-ASA from all the 5-ASA-delivering drugs is influenced unfavourably by an accelerated gut transit but most pronounced in the case of sulphasalazine, olsalazine, and Asacol. The impaired release from the azo compounds sulphasalazine and olsalazine is a result of far less complete splitting of the diazo bond.     

Anastomotic configuration and mucosal 5-aminosalicyclic acid (5-ASA) concentrations in patients with Crohn's disease: a GISC study. Gruppo Italiano per lo Studio del Colon e del Retto

OBJECTIVE: Recurrence of Crohn's disease quite inevitably occurs after resection of distal small bowel and proximal colon, involving the neoterminal ileum close to the anastomosis. Oral 5-aminosalicylic acid (5-ASA) administered soon after surgery delays recurrence and reduces its severity. We recently observed that in operated patients submitted to prophylactic treatment with oral 5-ASA the rate of recurrence was significantly higher in those with end-to-end anastomosis than in those with other types of anastomosis (end-to-side, side-to-side). The hypothesis investigated in the present study was that patients with end-to-side or side-to-side anastomosis would benefit from a higher mucosal concentration of 5-ASA with respect to patients with end-to-end anastomosis. Therefore, the mucosal 5-ASA concentration was measured in the perianastomotic area of both groups. METHODS: The study was carried out in 19 patients submitted to radical surgery for Crohn's ileitis or ileocolitis, under oral prophylactic treatment with 5-ASA (Asacol). All patients were on regular endoscopic follow-up and were free of recurrence. Two biopsies were collected 3 cm from the anastomosis, in the neoterminal ileum, and two biopsies were collected at the colonic site 3 cm below the anastomosis. 5-ASA concentrations (ng/mg) were measured in tissue homogenates by high-performance liquid chromatography (HPLC) with electrochemical detection. RESULTS: The mucosal concentration of 5-ASA in the neoterminal ileum was significantly lower in patients with end-to-end anastomosis than in those with other types of anastomosis (median values: 29.4 ng/mg vs 92.9 ng/mg respectively; p < 0.001). Six of 10 patients (60%) with end-to-end anastomosis, but none of the nine patients with other types of anastomosis, showed 5-ASA mucosal concentrations <40 ng/mg at the neoterminal ileum. On the contrary, no patients with end-to-end anastomosis showed mucosal concentrations of 5-ASA >90 ng/mg, compared with the 57% of patients in the group with other types of anastomosis. No differences were observed for colonic biopsies. CONCLUSIONS: The different mucosal concentrations in these two groups may be explained by the difference in segmental transit time induced by the different anastomotic configurations. A slower preanastomotic transit time, demonstrated in patients with end-to-side or side-to-side anastomosis, could offer a prolonged contact time between the intestinal content and the mucosa, resulting in an increase in drug absorption.     

5-ASA colonic mucosal concentrations resulting from different pharmaceutical formulations in ulcerative colitis

AIM:To compare the mucosal concentrations of 5-aminosalicylic acid(5-ASA)resulting from different pharmaceutical formulations and analyse the influence of inflammation on the mucosal concentrations.METHODS:The study included 130 inflammatory bowel disease(IBD)patients receiving 5-ASA as pH-dependent-release formulations(73 patients),time-dependent-release formulations(11 patients),or pro-drugs(18patients).In addition,28 patients were receiving topical treatment(2-4 g/d)with pH-dependent-release formulations.Endoscopic biopsies were obtained from the sigmoid region during the colonoscopy.The 5-ASA concentrations(ng/mg)were measured in tissue homogenatesusing high-pressure liquid chromatography with electrochemical detection.The t test and Mann-Whitney test,when appropriate,were used for statistical analysis.RESULTS:Patients receiving pH-dependent-release formulations showed significantly higher mucosal concentrations of 5-ASA(51.75±5.72 ng/mg)compared with patients receiving pro-drugs(33.35±5.78 ng/mg,P=0.01)or time-dependent-release formulations(38.24±5.53 ng/mg,P=0.04).Patients with endoscopic remission had significantly higher mucosal concentrations of5-ASA than patients with active disease(60.14±7.95ng/mg vs 35.66±5.68 ng/mg,P=0.02).Similar results were obtained when we compared patients with the histological appearance of remission and patients with active histological inflammation(67.53±9.22 ng/mg vs 35.53±5.63 ng/mg,P<0.001).Significantly higher mucosal concentrations of 5-ASA were detected in patients treated with both oral and topical treatments in combination compared with patients who received oral treatment with pH-dependent-release formulations alone(72.33±11.23 ng/mg vs 51.75±5.72 ng/mg,P=0.03).CONCLUSION:IBD patients showed significant variability in mucosal 5-ASA concentrations depending on the type of formulation,and the highest mean concentration was achieved using pH-dependent-release formulations.     

New oral salicylates in the therapy of chronic idiopathic inflammatory bowel disease

Sulfasalazine has been the mainstay of therapy for ulcerative colitis and Crohn's disease of the colon. More recently, it has become clear that 5-ASA is the active moiety of the compound and that the sulfapyridine component is responsible for most of the adverse responses to sulfasalazine. The modes of action of sulfasalazine and 5-ASA have not been determined despite active investigations. There has been great current emphasis on the development of delivery systems to allow maximum concentration of therapeutically active 5-ASA in the colon or other gastrointestinal mucosal locations. Olsalazine accomplishes this goal by creatively coupling two molecules of 5-ASA to each other by a diazo bond. Bacterial azoreductases uncouple the parent drug and deliver 5-ASA to the colonic mucosa. Several pharmaceutical manufacturers have devised variations in mesalamine (5-ASA) coatings designed to release in pH and time-related manners. Oral Rowasa, Claversal, and Asacol accomplish distal delivery with acrylic coating of tablets. Oral Pentasa seems unique in distributing 5-ASA throughout the small bowel as well as the colon by utilization of small ethylcellulose-coated microgranules. For this reason, Pentasa may be particularly useful in the treatment of small bowel Crohn's disease. There are no data to suggest that patients unresponsive to oral sulfasalazine will respond to 5-ASA in any form, although it is possible that better toleration of the 5-ASA formulations will allow more effective dosage levels to be delivered. There are also preliminary data supporting synergism between oral and topical rectal 5-ASA in certain patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Disposition of 5-aminosalicylic acid by 5-aminosalicylic acid-delivering compounds

The disposition of 5-aminosalicylic acid (5-ASA) from 5-ASA-delivering drugs was studied in eight healthy volunteers. Time-related urinary excretion and faecal excretion of 5-ASA and acetyl-5-ASA were measured after a single oral dose of the azo compounds sulphasalazine and olsalazine, of the slow-release compounds Pentasa, Asacol, and Salofalk, and of plain 5-ASA. Plain 5-ASA was rapidly excreted into urine and had a low faecal recovery, indicating fast absorption proximally in the intestine and little availability to the colon. After ingestion of both azo compounds and slow-release compounds, urinary excretion of 5-ASA was markedly delayed and reduced, and faecal excretion was enhanced. At all points of time there was a significant but not very marked difference in urinary excretion of 5-ASA after ingestion of the azo compounds and the slow-release compounds, in favour of the azo compounds. A significantly larger proportion of the ingested 5-ASA, moreover, was excreted in faeces after intake of azo compounds as compared with slow-release compounds.     

Bioavailability of 5-aminosalicylic acid from slow release 5-aminosalicylic acid drug and sulfasalazine in normal children

The bioavailability of a controlled release 5-aminosalicylic acid preparation (Pentasa) was investigated in nine healthy children after a medication period of six days (1000 mg/day) and compared with sulfasalazine (Salazopyrin) (2000 mg/day). The local bioavailability in the distal gut lumen, reflected by the 5-aminosalicylic acid concentration in the fecal water, showed comparable values after Pentasa (4.44 mmol/liter) and Salazopyrin (6.25 mmol/liter). The concentration ofN-acetyl-5-ASA was significantly higher after Pentasa, reflecting the more proximal release of 5-aminosalicylic acid compared with Salazopyrin. No relation was found between the 5-aminosalicylic acid fecal water concentration and the 5-aminosalicylic acid dose per kilogram of body weight. The urinary excretion of 5-aminosalicylic acid andN-acetyl-5-aminosalicylic acid was higher after Pentasa than after Salazopyrin (32% vs 25%). Dose interval plasma concentration curves showed low values after both preparations. Based on the concept that the fecal water concentration is decisive for the efficacy of 5-aminosalicylic acid in distal inflammatory bowel disease, Pentasa treatment offers a relevant alternative in cases of Salazopyrin intolerance or allergy in children. The higher systemic bioavailability from Pentasa warrants monitoring of the renal function.     

Current medical therapy of inflammatory bowel disease

The current established drugs used to treat inflammatory bowel disease include glucocorticoids includingnewer agent budesonide, sulfasalazine and 5-ASA compounds such as Asacol, Pentasa, Dipentum andBalsalazide and immunomodulatory agents such as azathioprine, and 6-mercaptopurine. Additional drugswhich have been found to be useful, particularly in refractory cases of Crohn's disease including fistulizingtype of Crohn's disease, include cyclosporine A, methotrexate, humanized antibody against TNFa(cA2),FK506, IL-10, IL-11 and Probiotics. Various agents, whether used alone or in combination, have to betailored for each patient and none is ideal. Exciting new developments directed against proinflammatorypathways, cytokines, free oxygen radicals and cell surface related immune targets are areas of intense recentinvestigations and many novel therapeutic agents are expected to be available in the near future for medicaltreatment of inflammatory bowel disease.     

Role of mesalazine in acute and long-term treatment of ulcerative colitis and its complications

BACKGROUND: Sulfasalazine, consisting of 5-aminosalicylic acid bound to sulfapyridine by a diazo bond, was first used for treatment of ulcerative colitis in the early 1940s and later found effective in placebo-controlled trials for acute disease and for long-term maintenance of remission. Later studies found that the active moiety is 5-ASA (mesalazine, mesalamine) and the sulfapyridine moiety acts as a carrier molecule but causes many of the symptomatic adverse reactions. METHODS: Review of the literature. RESULTS: The finding that 5-ASA in the active motility led to the development of mesalazine prodrugs, olsalazine (Dipentum) and balsalazide (Colazide, Colazal), and targeted release mesalazine preparations, such as Asacol, Pentasa, and Salofalk, as well as enemas and suppository preparations for distal disease. Most patients with adverse effects from sulfasalazine will tolerate mesalazine. Mesalazine has been shown equivalent or superior to sulfasalazine, and superior to placebo, with a dose-response benefit, in inducing remission of acute disease. and comparable to sulfasalazine and superior to placebo for long-term maintenance of remission. Better tolerance of mesalazine and the ability to use higher doses favor its use in patients intolerant of sulfasalazine and in patients failing to respond to usual doses of sulfasalazine. Adverse effects from mesalazine are uncommon, but include idiosyncratic worsening of the colitis symptoms and renal toxicity. Mesalazine is safe to use during pregnancy and for nursing mothers. As maintenance therapy, mesalazine may reduce the risk of developing colorectal carcinoma. CONCLUSION: Mesalazine represents effective and well-tolerated first-line therapy for mildly to moderately acute disease as well as for the long-term maintenance treatment in the patient with ulcerative colitis.     

Pharmacology and pharmacokinetics of 5-aminosalicylic acid

There is accumulating clinical evidence that 5-aminosalicylic acid (5-ASA), a primary metabolite of sulfasalazine (SAS), represents the therapeutic active moiety of the azo-compound SAS in the treatment of chronic inflammatory bowel disease (IBD). Since it is presumed that 5-ASA acts from the lumen of the intestine, it is important to know how much 5-ASA is released from its special galenic formulations. After liberation of 5-ASA in the terminal ileum (only slow release oral preparations of 5-ASA) and colon (5-ASA suppositories and enemas), 5-ASA is only partly absorbed. A major part of this 5-ASA is presystemically eliminated, eg, N-acetylated during its first passage through the intestinal mucosa and liver. Mean steady state plasma levels of unchanged 5-ASA are rather low (range 0.02 to 1.2 μg/ml) whereas those of Ac-5-ASA are always higher (range 0.1 to 2.9 μg/ml). This is due to the rapid elimination of 5-ASA (t1/2=0.4 to 2.4h) and the slightly slower renal excretion of the Ac-5-ASA (t1/2=6 to 9h, renal clearance=200 to 300 ml/min). The knowledge of the pharmacokinetic properties of 5-ASA from different drug formulations might contribute to a better understanding of its mode of action in IBD.     

5-ASA in ulcerative colitis： Improving treatment compliance

5-aminosalicylic acid （5-ASA） compounds are a highly effective treatment for ulcerative colitis （UC）. While UC patient compliance in clinical studies is over 90%, only 40% of patients in every day life take their prescribed therapy. Adherence to medication has been emphasized recently by a Cochrane meta-analysis that has suggested that future trials of 5-ASA in UC should look at patient compliance rather than drug efficacy. Better compliance can be obtained by reducing the number of tablets and times of administration. Given that the 5-ASA formulations have different delivery systems that split the active moiety in various regions of the intestine, it is particularly important that an adequate dose of the drug arrives at the inflamed part of the colon. 5-ASA Multi matrix （MMx） is a novel, high strength （1.2 g）, oral formulation designed for oncedaily dosing. It releases the active moiety throughout the colon. Different studies with this compound have shown that it is as effective as 5-ASA enema in the treatment of mild-to-moderate, left-sided UC, and is comparable to a pH-dependent, delayed release 5-ASA （Asacol）, even if given once daily. Recently, the effectiveness in the acute phase of UC has been confirmed also in maintenance. In conclusion, at present, 5-ASA MMx seems theoretically the best agent for maintaining patient compliance, and consequently, treatment effectiveness.     

Effect of aminophenols (5-ASA and 4-ASA) on colonic interleukin-1 generation.

The effect of 5-ASA and 4-ASA, drugs used for the treatment of inflammatory bowel disease, on modulation of experimental colitis and on colonic generation of interleukin-1 was evaluated. Three weeks of treatment with 5-ASA or 4-ASA (50 micrograms/kg) and one week of treatment with 5-ASA significantly decreased colonic interleukin-1 generation and the extent and severity of inflammation in a rat model of colitis induced by trinitrobenzene sulphonic acid. Colonic biopsies were obtained from patients with active ulcerative colitis and organ cultured 24 hours in the absence or presence of the following drugs: sulphasalazine, sulphapyridine, 5-ASA and 4-ASA (25-100 micrograms/ml). Interleukin-1 content in tissue cultured in the presence of 5-ASA (100 micrograms/ml) was two-thirds of its content in tissue cultured in drug free medium and its release into the medium was decreased by 50%. Sulphasalazine 50 micrograms/ml significantly decreased by 33% the tissue content but did not affect interleukin-1 release and a higher dose was not more effective. Sulphapyridine and 4-ASA in doses up to 100 micrograms/ml did not affect either interleukin-1 colonic content or its release into the culture medium. We conclude that pharmacological suppression of colonic interleukin-1 generation may be one, although not the sole mechanism to explain the therapeutic efficacy of 5-ASA in the treatment of inflammatory bowel disease.     

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.     

A dynamic model of once-daily 5-aminosalicylic acid predicts clinical efficacy

New once daily mesalamine formulations may improve adherence to medication usage.Response to Asacol and other forms of 5-aminosalicyclic acid(5-ASA)is better correlated with tissue concentrations and best predicted by concentrations of the drug within the lumen of the colon.Our group used computer simulation to predict colonic 5-ASA levels after Asacol administration.In our study,the model simulated Asacol distribution in the healthy colon,and during quiescent and active ulcerative colitis.An Asacol dosage ...     

A dynamic model of once-daily 5-aminosalicylic acid predicts clinical efficacy

New once daily mesalamine formulations may improve adherence to medication usage.Response to Asacol and other forms of 5-aminosalicyclic acid(5-ASA)is better correlated with tissue concentrations and best predicted by concentrations of the drug within the lumen of the colon.Our group used computer simulation to predict colonic 5-ASA levels after Asacol administration.In our study,the model simulated Asacol distribution in the healthy colon,and during quiescent and active ulcerative colitis.An Asacol dosage ...     

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.     

Effect of polymer coating on faecal recovery of ingested 5-amino salicylic acid in patients with ulcerative colitis.

It has been suggested that polymer coating might retard jejunal absorption of 5-amino salicylic acid (5-ASA) and thus promote delivery to its colonic site of action. Twenty three patients with active (nine), or quiescent (14) ulcerative colitis were given either uncoated or coated 5-ASA (Asacol) 400 mg qds for one to three weeks, after which they ingested five 1.5 ml dialysis membrane sachets which were recovered from the stool in the next 72 hours. After one week of treatment the concentration of 5-ASA in the faecal dialysate, urine, and fasting plasma in those receiving the coated and uncoated preparations were respectively: 25.4 +/- 5.1 compared with 1.2 +/- 0.4 mmol/l (p less than 0.001); 0.34 +/- 0.21 compared with 0.70 +/- 0.29 mmol/24h (NS) and 11.1 +/- 4.2 compared with 0.07 +/- 0.03 mumol/l (p less than 0.02). Faecal excretion of the drug appeared to be greater in patients with active colitis than in those with quiescent disease. Thus coating with pH dependent methacrylic acid copolymer B is a very effective method of promoting delivery of 5-ASA to the colon, stool dialysate concentrations being 20 fold more than those in controls. Increased trough plasma concentrations in the polymer coating group probably reflect delayed intestinal absorption but no evidence of plasma accumulation after 21 days of therapy was found.     

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)