Regional jejunal perfusion, a new in vivo approach to study oral drug absorption in man.

Recently a new in vivo approach in man, using a regional intestinal perfusion technique, has been developed. The perfusion tube consists of a multichannel tube with two inflatable balloons, which are placed 10 cm apart. The tube is introduced orally and the time required for insertion and positioning of the tube is approximately 1 hr. In the present study eight healthy subjects were perfused in the proximal jejunum on three separate occasions. The first two perfusion experiments used the same flow rate, 3 ml/min, and the third experiment used 6 ml/min. Phenazone (antipyrine) was chosen as the model drug. The recovery of PEG 4000 in the outlet intestinal perfusate was complete in experiments 1 and 2, but slightly lower (90%) when the higher flow rate was used. The mean (+/- SD) fraction of phenazone absorbed calculated from perfusion data was 51 +/- 12% (3 ml/min), 64 +/- 19% (3 ml/min), and 42 +/- 27% (6 ml/min) for the three experiments, respectively. The mean fraction absorbed estimated by deconvolution of the plasma data was 47 +/- 16%, 51 +/- 19%, and 38 +/- 26%, respectively. The effective permeability of phenazone was 5.3 +/- 2.5, 11 +/- 6.8, and 11 +/- 12 (x 10(4) cm/sec, respectively. We have shown that it was possible to establish a tight intestinal segment which behaved as a well-mixed compartment. The low perfusion rate of 3 ml/min was preferred, since it resulted in the lowest variability in absorption.(ABSTRACT TRUNCATED AT 250 WORDS)

Relative bioavailability of olsalazine from tablets and capsules: a drug targeted for local effect in the colon.

The aim of this investigation was to compare two formulations of the prodrug olsalazine (OLZ) with regard to local bioavailability of 5-aminosalicylic acid (5-ASA) in the colon. Since 5-ASA can not be measured directly in the colon, the bioavailability was evaluated by studying the plasma concentration and cumulative urinary excretion (Ae) of its main metabolite N-acetyl-5-aminosalicylic acid (ac-5-ASA). The absorption of OLZ was also studied. A single dose of 1g OLZ tablets and capsules was given to nine healthy fasting volunteers in two repeated two-period cross-over studies. Blood and urine samples were collected for 72 and 96 h, respectively. AUC, Cmax and Ae data from both studies were combined for statistical analysis. Ninety per cent confidence limits for differences in mean AUC for ac-5-ASA (tablet-capsule) compared to that of capsules were -0.31 per cent and 30.8 per cent. This indicates bioequivalence if a more relaxed criterion than the conventional +/- 20 per cent is applied, which is justified in this situation. The 90 per cent confidence limits for Cmax were -10.5 per cent and 36.9 per cent while for Ae the values were -20.5 per cent and 23.7 per cent. Within and between subject variability estimates for AUC of ac-5-ASA were 24 per cent and 46 per cent, respectively.

Biliary excretion of olsalazine sodium in humans.

The biliary excretion of Olsalazine sodium (ADS) was studied by three different methods in healthy volunteers and in patients. 1 g ADS in a 2% solution was infused during 1 h into jejunum in six healthy volunteers via a three lumen sond. The bile was collected, during 2.5-6 h, proximal of an occlusive balloon on the three lumen sond. 10 mg ADS was given i.v. to five healthy volunteers and the bile was collected during 3-4.5 h with the same type of three lumen sond as used in the first experiment. 1 g ADS was given orally to three patients, with a T-tube inserted into coleducus at surgery. The bile was collected via the T-tube for 24 h. The mean biliary excretion of the jejunal dose was 0.41% (0.22% if one subject, who probably had a beckflow of the instillation fluid, is omitted). In patients, the mean excretion with bile of ADS was 0.35% and of ac-5-ASA 0.17%. Due to the short collection time after jejunal infusion and the probably incomplete collection of bile in both enteral studies the biliary excretion was estimated to be less than 2% as ADS and less than 1% as ac-5-ASA. The biliary excretion of an i.v. dose showed large individual variations (0.16-12.2%) which were not correlated to the length of the collection time. The total excretion was estimated to be less than 20% as ADS. No metabolites were detected after the i.v. dose.

Effect of olsalazine sodium on migrating motor complexes in the upper small bowel of human volunteers.

The effect of a peroral dose of olsalazine sodium on the migrating motor complexes (MMC) in the upper small bowel was studied by manometry in nine healthy volunteers during fasting. Recordings were obtained from the duodenum and/or the upper jejunum for 4.0 - 7.5 h. During total baseline observation periods of 30 h, fourteen MMCs could be identified compared to ten complexes during post dose registrations of 25 h. This gives an average mean interval for baseline pre dose complexes of 2.2 h, and for post dose complexes 2.5 h. If excluding the two subjects, who had the longest interval until the first MMC before dosing and did not present any MMC after dosing, the corresponding figures are 1.9 h and 1.9 h, respectively. Although our material is small with respect to the large individual variation in the recordings the results indicate that MMC does occur after an olsalazine sodium dose which is twice the dose normally recommended. Besides we can conclude that there is no apparent interference with the time for MMC occurrence in the upper small bowel in fasting humans.

Effect of azodisal sodium on the distribution of a transit marker in the small bowel of the fasted rat.

The effect of azodisal sodium (ADS) on the transit of a radioactive marker in the small bowel was compared with that of 5-ASA and sulfasalazine (SASP). The bile-excreted radiopharmaceutic 99mTc-HIDA was infused intravenously for 1 h into conscious rats with an intact alimentary tract and the radioactivity along the excised gastrointestinal specimen was subsequently determined. After administration of ADS (12.5 mg/rat), 5-ASA and SASP, the distribution of radioactivity was characterized by localized peaks of radioactivity separated by fairly long empty regions. As judged from experience this pattern represents the fasting state under control conditions. Administration of ADS (60 and 120 mg/rat) resulted in a distribution along the small bowel without any apparent peaks or empty regions. The transport rate of the front of the tracer was enhanced by ADS at higher doses but not by 5-ASA or SASP. Intravenous administration of ADS did not affect the transit, indicating the importance of the presence of ADS in the gut lumen. Prostaglandin release does not seem to be a probable mediating mechanism since pretreatment with indomethacin did not abolish the effect of ADS on the interdigestive transit pattern.

Colonic azodisalicylate metabolism determined by in vivo dialysis in healthy volunteers and patients with ulcerative colitis.

Azodisalicylate, a second generation drug of sulfasalazine, delivers twice the amount of 5-aminosalicylic acid to the colonic lumen on a molar basis when split by bacterial azoreductases. In 6 patients with inactive ulcerative colitis, the colonic metabolism of sulfasalazine and azodisalicylate was studied by equilibrium in vivo dialysis of feces to measure the therapeutically relevant concentrations of their metabolites (5-aminosalicylic acid and N-acetyl-5-aminosalicylic acid) in free fecal water. After oral intake of sulfasalazine (2 g/day) the total luminal concentrations of 5-aminosalicylic acid and N-acetyl-5-aminosalicylic acid determined by high-performance liquid chromatography were higher (median 14 mmol/L) than previously reported and almost doubled (median 25 mmol/L, p less than 0.05) when sulfasalazine was replaced by the same dose of azodisalicylate. In contrast, the corresponding serum concentrations were negligible. After administration of azodisalicylate to 12 healthy volunteers, a similar distribution of the metabolites was found. In nearly all cases, the concentrations of azodisalicylate in fecal dialysates were below the detection limit (6 mumol/L). We conclude, therefore, that oral azodisalicylate is a highly effective means of delivery of 5-aminosalicylic acid to the colonic mucosa. In addition, determination of the active metabolites in free fecal water seems important for the interpretation of results obtained in vitro concerning the mode of drug action.

Absorption and excretion of azodisal sodium and its metabolites in man after rectal administration of a single 2-g dose.

The behaviour of azodisal sodium (ADS) and its metabolites after a single 2-g rectal dose was investigated in 10 healthy volunteers. Blood samples were drawn frequently, and urine was collected during intervals of 24 h. The ADS absorption gave a mean peak serum concentration of 2.1 (SD +/- 0.7) microgram/ml. The urinary excretion of ADS was 0.8% of the given dose. After rectal administration 5-aminosalicylic acid (5-ASA) could be detected in the serum only in two of the subjects, with a mean concentration of less than 0.5 microgram/ml. Ac-5-ASA was present in increasing serum concentrations, being 0.93 microgram/ml at 24 h. The mean 24-h urinary excretion of these two metabolites was only 2.7% of the given dose. In another study the azo bond of ADS has been shown to be split by anaerobic and aerobic bacteria. The low absorption of its metabolites indicates that ADS is a suitable molecule for delivering the presumed pharmacologically active moiety, 5-ASA.

Absorption and excretion of a single 1-g dose of azodisal sodium in subjects with ileostomy.

The behaviour of a single 1-g oral dose of azodisal sodium (ADS) given to 10 healthy volunteers with an ileostomy was studied. Blood samples were drawn at various times, and urine and ileostomy fluid were collected during the following 24 h. ADS was absorbed to a very low extent, giving a maximum serum concentration of less than or equal to 5.1 micrograms/ml within 0.5-2 h after the dose was ingested. A mean of 0.3% of the dose was excreted in unchanged form with the urine. The metabolites 5-ASA and Ac-5-ASA could not be found in serum or urine. Of the ADS dose given, 100.2% (SD +/- 14.8%) could be recovered in the ileostomy fluid. The results indicate that ADS is a potentially useful drug for the local treatment of ulcerative colitis, 5-ASA being the active part of the molecule.