Degradation kinetics of metronidazole and olsalazine by bacteria in ascending colon and in feces of healthy adults.

PURPOSE To compare the degradation kinetics of metronidazole and olsalazine by the bacteria of ascending colon and the bacteria of feces of healthy adults. METHODS Contents of the ascending colon of seven healthy adults were collected under conditions simulating the bioavailability/bioequivalence studies in the fasted and in the fed states on a crossover basis. Material from the contents of the ascending colon was prepared by ultracentrifuging and diluting the precipitate with a volume of normal saline equivalent to that of the supernatant. Fecal material was prepared from feces of three healthy adults collected at two occasions that were separated by at least 6 months. Ex vivo drug degradation kinetics were evaluated under anaerobic conditions. RESULTS Mean half-lives of metronidazole degradation in material from the contents of the ascending colon collected in the fasted state and in fecal material were 16.1 and 2.4 min, respectively (p<0.001). The corresponding numbers for olsalazine were 57.8 and 9.2 min, respectively (p<0.001). Both compounds were stable in material from the contents of ascending colon collected in the fed state. CONCLUSIONS Compared with data in fecal material, degradation of metronidazole and olsalazine in material from the contents of the ascending colon is significantly slower and it becomes non-significant during the arrival of fresh food remnants in the region.

[1]  Abdul W Basit,et al.  The gastrointestinal microbiota as a site for the biotransformation of drugs. , 2008, International journal of pharmaceutics.

[2]  D. Burdon,et al.  Influence of bowel preparation and antimicrobials on colonic microflora , 1978, The British journal of surgery.

[3]  J. Rask-Madsen,et al.  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. , 1990, Gut.

[4]  G. Tannock.  Analysis of the intestinal microflora: a renaissance , 1999, Antonie van Leeuwenhoek.

[5]  S. Hanauer,et al.  The pharmacokinetic profiles of oral mesalazine formulations and mesalazine pro‐drugs used in the management of ulcerative colitis , 2003, Alimentary pharmacology & therapeutics.

[6]  Sanjay K. Jain,et al.  Azo chemistry and its potential for colonic delivery. , 2006, Critical reviews in therapeutic drug carrier systems.

[7]  Christos Reppas,et al.  Characterization of the Contents of Ascending Colon to Which Drugs are Exposed After Oral Administration to Healthy Adults , 2009, Pharmaceutical Research.

[8]  J. Wagner.  Pharmacokinetics for the Pharmaceutical Scientist , 1993 .

[9]  P. Goldman,et al.  Acetamide--a metabolite of metronidazole formed by the intestinal flora. , 1979, Biochemical pharmacology.

[10]  M. Yeh,et al.  Degradation kinetics of metronidazole in solution. , 1993, Journal of pharmaceutical sciences.

[11]  P. Mortensen,et al.  Colonic fermentation of ispaghula, wheat bran, glucose, and albumin to short-chain fatty acids and ammonia evaluated in vitro in 50 subjects. , 1992, JPEN. Journal of parenteral and enteral nutrition.

[12]  A. Renwick,et al.  The reduction of sulphinpyrazone and sulindac by intestinal bacteria. , 1987, Xenobiotica; the fate of foreign compounds in biological systems.

[13]  N. Ahnfelt,et al.  The pharmacokinetics of olsalazine sodium in healthy volunteers after a single i.v. dose and after oral doses with and without food , 2004, European Journal of Clinical Pharmacology.

[14]  C. Neut,et al.  Bacterial enzymes used for colon-specific drug delivery are decreased in active Crohn's disease , 1995, Digestive Diseases and Sciences.

[15]  L. Bodin,et al.  Relation between concentrations of metronidazole and Bacteroides spp in faeces of patients with Crohn's disease and healthy individuals. , 1981, Journal of clinical pathology.

[16]  R. Willén,et al.  Impairment of bacterial flora in human ulcerative colitis and experimental colitis in the rat. , 1993, Digestion.

[17]  M. Shamat.  The role of the gastrointestinal microflora in the metabolism of drugs , 1993 .

[18]  C. Edmiston,et al.  Anaerobic bacterial populations on normal and diseased human biopsy tissue obtained at colonoscopy , 1982, Applied and environmental microbiology.

[19]  O. Hernell,et al.  Physical-chemical behavior of dietary and biliary lipids during intestinal digestion and absorption. 2. Phase analysis and aggregation states of luminal lipids during duodenal fat digestion in healthy adult human beings. , 1990, Biochemistry.

[20]  C. Neut,et al.  Impaired bacterial flora in human excluded colon. , 1989, Gut.

[21]  Hans Lennernäs,et al.  Toward an increased understanding of the barriers to colonic drug absorption in humans: implications for early controlled release candidate assessment. , 2009, Molecular pharmaceutics.

[22]  C. Hawkey,et al.  Mucosally associated bacterial flora of the human colon: quantitative and species specific differences between normal and inflamed colonic biopsies , 1999 .

[23]  L. Lacey,et al.  Colonic metabolism of ranitidine: implications for its delivery and absorption. , 2001, International journal of pharmaceutics.

[24]  T. Borody,et al.  Sulfapyridine appearance in plasma after salicylazosulfapyridine , 1986 .

[25]  M. Treat,et al.  Effect of polyethylene glycol-electrolyte lavage solution on intestinal microflora , 1989, Applied and environmental microbiology.

[26]  I. Rowland.  Factors affecting metabolic activity of the intestinal microflora. , 1988, Drug metabolism reviews.

[27]  R. Spiller,et al.  The stability of amoxycillin, clarithromycin and metronidazole in gastric juice: relevance to the treatment of Helicobacter pylori infection. , 1997, The Journal of antimicrobial chemotherapy.

[28]  A. Vince,et al.  Effect of lactulose on ammonia production in a fecal incubation system. , 1978, Gastroenterology.