The gastrointestinal microbiota as a site for the biotransformation of drugs

International Journal of Pharmaceutics

Volumn 363, Issue 1-2, 2008, Pages 1-25

  Sousa, Tiago ^a   Paterson, Ronnie ^b   Moore, Vanessa ^b   Carlsson, Anders ^c   Abrahamsson, Bertil ^c   Basit, Abdul W ^a  

^a UNIVERSITY OF LONDON   (United Kingdom)

^b ASTRAZENECA   (United Kingdom)

^c ASTRAZENECA R AND D   (Sweden)

Author keywords

Bacteria; Bioavailability; Colonic delivery; Fermentation; Large intestine; Metabolism; Microbiota; Microflora; Stability; Xenobiotics

Indexed keywords

BALSALAZIDE; CALCITONIN; CARBOHYDRATE; CHLORAMPHENICOL; CLONAZEPAM; DIGOXIN; DRUG METABOLITE; GLYCERYL TRINITRATE; INSULIN; ISOSORBIDE DINITRATE; LACTULOSE; LEVAMISOLE; LEVODOPA; MESALAZINE; METRONIDAZOLE; MISONIDAZOLE; NITRAZEPAM; NIZATIDINE; OLSALAZINE; OMEPRAZOLE; PHENACETIN; RANITIDINE; SALAZOSULFAPYRIDINE; SORIVUDINE; SUCCINYLSULFATHIAZOLE; SULFAMIDOCHRYSOIDINE; SULFINPYRAZONE; SULINDAC; UNINDEXED DRUG; ZONISAMIDE;

BACTERIAL METABOLISM; BONE MARROW APLASIA; DEACETYLATION; DEGLYCOSYLATION; DRUG ACETYLATION; DRUG DEGRADATION; DRUG HYDROLYSIS; DRUG PENETRATION; DRUG RELEASE; DRUG SOLUBILITY; DRUG STABILITY; DRUG TRANSFORMATION; ENZYME RELEASE; FERMENTATION; HUMAN; INTESTINE FLORA; NONHUMAN; PRIORITY JOURNAL; PROTEIN DEGRADATION; REDUCTION; REVIEW; RING OPENING;

ADMINISTRATION, ORAL; ANIMALS; BACTERIA; BACTERIAL PROTEINS; BIOLOGICAL AVAILABILITY; BIOTRANSFORMATION; DRUG INTERACTIONS; DRUG STABILITY; GASTROINTESTINAL TRACT; HUMANS; INTESTINAL ABSORPTION; PHARMACEUTICAL PREPARATIONS; SUBSTRATE SPECIFICITY;

EID: 50849084986     PISSN: 03785173     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.ijpharm.2008.07.009     Document Type: Review

References (140)

1. Abu Shamat M. The role of the gastrointestinal microflora in the metabolism of drugs. Int. J. Pharm. 97 (1993) 1-13
2. Abu Shamat M.S., and Beckett A.H. Glyceryl trinitrate: metabolism by the intestinal flora. J. Pharm. Pharmacol. 35 (1983) 71P
3. Adlercreutz H., and Martin F. Biliary excretion and intestinal metabolism of progesterone and estrogens in man. J. Steroid Biochem. 13 (1980) 231-244
4. Allison C., McFarlan C., and MacFarlane G.T. Studies on mixed populations of human intestinal bacteria grown in single-stage and multistage continuous culture systems. Appl. Environ. Microbiol. 55 (1989) 672-678
5. Amidon G.L., Lennernäs H., Shah V.P., and Crison J.R. A theoretical basis for a biopharmaceutics drug classification: The correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm. Res. 12 (1995) 413-420
6. Ashida N., Ijichi K., Watanabe Y., and Machida H. Metabolism of 5′-ether prodrugs of 1-β-d-arabinofuranosyl-e-5(2-bromovinyl)uracil in rats. Biochem. Pharmacol. 46 (1993) 2201-2207
7. Bachrach W.H. Sulfasalazine: I. An historical perspective. Am. J. Gastroenterol. 83 (1988) 487-496
8. Basit A.W. Advances in colonic drug delivery. Drugs 65 (2005) 1991-2007
9. Basit A.W., and Lacey L.F. Colonic metabolism of ranitidine: implications for its delivery and absorption. Int. J. Pharm. 227 (2001) 157-165
10. 2-receptor antagonists cimetidine, famotidine and nizatidine, to metabolism by the gastrointestinal microflora. Int. J. Pharm. 237 (2002) 23-33
11. Basit A.W., Podczeck F., Newton J.M., Waddington W.A., Ell P.J., and Lacey L.F. The use of formulation technology to assess regional gastrointestinal drug absorption in humans. Eur. J. Pharm. Sci. 21 (2004) 179-189
12. Burkitt D.P., Walker A.R., and Painter N.S. Effect of dietary fibre on stools and the transit-times, and its role in the causation of disease. Lancet 2 (1972) 1408-1412
13. Caldwell J., and Hawksworth G.M. The demethylation of methamphetamine by intestinal microflora. J. Pharm. Pharmacol. 25 (1973) 422-424
14. Celesk R.A., Asano T., and Wagner M. The size, pH and redox potential of the cecum in mice associated with various microbial floras. Proc. Soc. Exp. Biol. Med. 151 (1976) 260-263
15. Chan R.P., Pope D.J., Gilbert A.P., Sacra P.J., Baron J.H., and Lennard-Jones J.E. Studies of two novel sulfasalazine analogs, ipsalazide and balsalazide. Dig. Dis. Sci. 28 (1983) 609-615
16. Cinquin C., Le Blay G., Fliss I., and Lacroix C. Immobilization of infant fecal microbiota and utilization in an in vitro colonic fermentation model. Microb. Ecol. 48 (2004) 128-138
17. Coates M.E., Drasar B.S., Mallett A.K., and Rowland I.R. Methodological considerations for the study of bacterial metabolism. In: Rowland I.R. (Ed). Role of the Gut Flora in Toxicity and Cancer (1988), Academic Press, London
18. Cummings J.H., Antoine J.-M., Azpiroz F., Bourdet-Sicard R., Brandtzaeg P., Calder P.C., Gibson G.R., Guarner F., Isolauri E., Pannemans D., Shortt C., Tuijtelaars S., and Watzl B. Passclaim-gut health and immunity. Eur. J. Nutr. 43 (2004) 118-173
19. Cummings J.H., Bingham S.A., Heaton W., and Eastwood M.A. Fecal weight, colon cancer risk, and dietary intake of nonstarch polysaccharides (dietary fiber). Gastroenterology 103 (1992) 1783-1789
20. Cummings J.H., Hill M.J., Bone E.S., Branch W.J., and Jenkins D.J. The effect of meat protein and dietary fiber on colonic function and metabolism. II. Bacterial metabolites in feces and urine. Am. J. Clin. Nutr. 32 (1979) 2094-2101
21. Cummings J.H., and Macfarlane G.T. Role of intestinal bacteria in nutrient metabolism. JPEN J. Parenter. Enteral Nutr. 21 (1997) 357-365
22. Cummings J.H., Macfarlane G.T., and Drasar B.S. The gut microflora and its significance. In: Whitehead R. (Ed). Gastrointestinal and Oesophageal Pathology (1989), Churchill Livingstone, London
23. Davis S.S. Formulation strategies for absorption windows. Drug Discov. Today 10 (2005) 249-257
24. De Boever P., Deplancke B., and Verstraete W. Fermentation by gut microbiota cultured in a simulator of the human intestinal microbial ecosystem is improved by supplementing a soygerm powder. J. Nutr. 130 (2000) 2599-2606
25. Deloménie C., Fouix S., Longuemaux S., Brahimi N., Bizet C., Picard B., Denamur E., and Dupret J.-M. Identification and functional characterization of arylamine n-acetyltransferases in eubacteria: evidence for highly selective acetylation of 5-aminosalicylic acid. J. Bacteriol. 183 (2001) 3417-3427
26. Drasar B.S., and Barrow P.A. The bacterial flora of the normal intestine. In: Barrow P.A. (Ed). Intestinal Microbiology (1985), Van Nostrand Reinhold, Wokingham
27. Drasar B.S., Hill M.J., and Williams R.E.O. The significance of the gut flora in safety testing of food additives. In: Roe F.J.C. (Ed). Metabolic Aspects of Food Safety (1970), Academic, New York
28. Dressman J.B., Amidon G.L., Reppas C., and Shah V.P. Dissolution testing as a prognostic tool for oral drug absorption: immediate release dosage forms. Pharm. Res. 15 (1998) 11-22
29. Dull B.J., Salata K., and Goldman P. Role of the intestinal flora in the acetylation of sulphasalazine metabolites. Biochem. Pharmacol. 36 (1987) 3772-3774
30. Eckburg P.B., Bik E.M., Bernstein C.N., Purdom E., Dethlefsen L., Sargent M., Gill S.R., Nelson K.E., and Relman D.A. Diversity of the human intestinal microbial flora. Science 308 (2005) 1635-1638
31. Edwards C.A., and Parrett A.M. Colonic fermentation-in vitro and in vivo approaches to measurement. Sci. Aliment. 19 (1999) 291-300
32. Egert M., de Graaf A.A., Smidt H., de Vos W.M., and Venema K. Beyond diversity: functional microbiomics of the human colon. Trends Microbiol. 14 (2006) 86-91
33. Elkington S.G., Floch M.H., and Conn H.O. Lactulose in the treatment of chronic portal-systemic encephalopathy. N. Engl. J. Med. 281 (1969) 408-412
34. Elmer G.W., and Remmel R.P. Role of intestinal microflora in clonazepam metabolism in the rat. Xenobiotica 14 (1984) 829-840
35. Escherich T. Die darmbakterien des neugeborenen und sauglings. Fortschr. Med. 3 (1885) 447-547
36. Evans D.F., Pye G., Bramley R., Clark A.G., Dyson T.J., and Hardcastle J.D. Measurement of gastrointestinal ph profiles in normal ambulant human subjects. Gut 29 (1988) 1035-1041
37. Fanaro S., Chierici R., Guerrini P., and Vigi V. Intestinal microflora in early infancy: composition and development. Acta Paediatr. 92 (2003) 48-55
38. Finegold S.M., Sutter V.L., and Mathisen G.E. Normal and indigenous flora. In: Hentges D.J. (Ed). Human Intestinal Microflora in Health and Disease (1983), Academic Press, New York
39. Fouts J.R., Kamm J.J., and Brodie B.B. Enzymatic reduction of prontosil and other azo dyes. J. Pharmacol. Exp. Ther. 120 (1957) 291-300
40. Fuller A.T. Is p-aminobenzenesulphonamide the active agent in prontosil therapy?. Lancet 1 (1937) 194-198
41. Gibson G.R., Cummings J.H., and Macfarlane G.T. Use of a three-stage continuous culture system to study the effect of mucin on dissimilatory sulfate reduction and methanogenesis by mixed populations of human gut bacteria. Appl. Environ. Microbiol. 54 (1988) 2750-2755
42. Gibson G.R., and Fuller R. Aspects of in vitro and in vivo research approaches directed toward identifying probiotics and prebiotics for human use. J. Nutr. 130 (2000) 391S-395S
43. Gibson G.R., and Wang X. Regulatory effects of bifidobacteria on the growth of other colonic bacteria. J. Appl. Bacteriol. 77 (1994) 412-420
44. Gingell R., Bridges J.W., and Williams R.T. The role of the gut flora in the metabolism of prontosil and neoprontosil in the rat. Xenobiotica 1 (1971) 143-156
45. Goldin B.R., Peppercorn M.A., and Goldman P. Contributions of host and intestinal microflora in the metabolism of l-dopa by the rat. J. Pharmacol. Exp. Ther. 186 (1973) 160
46. Goldman P. Gnotobiotic rats in studies of drug metabolism. In: Coates M.E., and Gustafsson B.E. (Eds). The Germ-free Animal in Biomedical Research (1984), Laboratory Animals Ltd., London
47. Gorbach S.L., Nahas L., Weinstein L., Levitan R., and Patterson J.F. Studies of intestinal microflora. IV. The microflora of ileostomy effluent: a unique microbial ecology. Gastroenterology 53 (1967) 874-880
48. Harris B.E., Manning B.W., Federle T.W., and Diasio R.B. Conversion of 5-fluorocytosine to 5-fluorouracil by human intestinal microflora. Antimicrob. Agents Chemother. 29 (1986) 44-48
49. Hayllar J., and Bjarnason I. Sulphasalazine in ulcerative colitis: in memoriam?. Gut 32 (1991) 462-463
50. Heneghan J.B. Physiology of the alimentary tract. In: Coates M.E., and Gustafsson B.E. (Eds). The Germ-free Animal in Biomedical Research (1984), Laboratory Animals Ltd., London
51. Hill M.J. Intestinal flora and endogenous vitamin synthesis. Eur. J. Cancer Prev. 6 (1997) S43-S45
52. Holt R. The bacterial degradation of chloramphenicol. Lancet 1 (1967) 1259
53. Ibekwe V.C., Liu F., Fadda H.M., Khela M.K., Evans D.F., Parsons G.E., and Basit A.W. An investigation into the in vivo performance variability of pH responsive polymers for ileo-colonic drug delivery using gamma scintigraphy in humans. J. Pharm. Sci. 95 (2006) 2760-2766
54. Ibekwe V.C., Fadda H.M., McConnell E.L., Khela M.K., Evans D.F., and Basit A.W. Interplay between intestinal pH, transit time and feed status on the in vivo performance of ph responsive ileo-colonic release systems. Pharm. Res. 25 (2008) 1828-1835
55. Ilett K.F., Tee L.B.G., Reeves P.T., and Minchin R.F. Metabolism of drugs and other xenobiotics in the gut lumen and wall. Pharmacol. Ther. 46 (1990) 67-93
56. Khoshini R., Dai S.-C., Lezcano S., and Pimentel M. A systematic review of diagnostic tests for small intestinal bacterial overgrowth. Dig. Dis. Sci. November (2007) (online version)
57. Kitamura S., Sugihara K., Kuwasako M., and Tatsumi K. The role of mammalian intestinal bacteria in the reductive metabolism of zonisamide. J. Pharm. Pharmacol. 49 (1997) 253-256
58. Koch R.L., Beaulieu B.B., and Goldman P. Role of the intestinal flora in the metabolism of misonidazole. Biochem. Pharmacol. 29 (1980) 3281-3284
59. Koch R.L., Beaulieu Jr. B.B., Chrystal E.J.T., and Goldman P. A metronidazole metabolite in human urine and its risk. Science 211 (1981) 398-400
60. Koch R.L., Chrystal E.J.T., Beaulieu Jr. B.B., and Goldman P. Acetamide-a metabolite of metronidazole formed by the intestinal flora. Biochem. Pharmacol. 28 (1979) 3611-3615
61. Koch R.L., and Goldman P. The anaerobic metabolism of metronidazole forms n-(2-hydroxyethyl)-oxamic acid. J. Pharmacol. Exp. Ther. 208 (1979) 406-410
62. Lee N.K., Choi S.H., Park S.H., Park E.K., and Kim D.H. Antiallergic activity of hesperidin is activated by intestinal microflora. Pharmacology 71 (2004) 174-180
63. Lennernäs H., and Abrahamsson B. The use of biopharmaceutic classification of drugs in drug discovery and development: current status and future extension. J. Pharm. Pharmacol. 57 (2005) 273-285
64. Ley R.E., Peterson D.A., and Gordon J.I. Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell 124 (2006) 837-848
65. Lindahl A., Ungell A.-L., Knutson L., and Lennernas H. Characterization of fluids from the stomach and proximal jejunum in men and women. Pharm. Res. 14 (1997) 497-502
66. Lindenbaum J., Rund D.G., Butler Jr. V.P., Tse-Eng D., and Saha J.R. Inactivation of digoxin by the gut flora: reversal by antibiotic therapy. N. Engl. J. Med. 305 (1981) 789-794
67. Macfarlane G.T., Cummings J.H., Macfarlane S., and Gibson G.R. Influence of retention time on degradation of pancreatic enzymes by human colonic bacteria grown in a 3-stage continuous culture system. J. Appl. Bacteriol. 67 (1989) 520-527
68. Macfarlane G.T., and Macfarlane S. Human colonic microbiota: ecology, physiology and metabolic potential of intestinal bacteria. Scand. J. Gastroenterol. 222 Suppl. (1997) 3-9
69. Macfarlane G.T., Macfarlane S., and Gibson G.R. Validation of a three-stage compound continuous culture system for investigating the effect of retention time on the ecology and metabolism of bacteria in the human colon. Microb. Ecol. 35 (1998) 180-187
70. Macfarlane S., and Macfarlane G.T. Bacterial diversity in the human gut. Adv. Appl. Microbiol. 54 (2004) 261-289
71. Magnusson J.O., Bergdahl B., Bogentoft C., and Johnsson U.E. Metabolism of digoxin and absorption site. Br. J. Clin. Pharmacol. 14 (1982) 284-285
72. Manning B.W., Campbell W.L., Franklin W., Delclos K.B., and Cerniglia C.E. Metabolism of 6-nitrochrysene by intestinal microflora. Appl. Environ. Microbiol. 54 (1988) 197-203
73. Marsh P.D. The role of continuous culture in modelling the human microflora. J. Chem. Technol. Biotechnol. 64 (1995) 1-9
74. McBain A.J., and Macfarlane G.T. Ecological and physiological studies on large intestinal bacteria in relation to production of hydrolytic and reductive enzymes involved in formation of genotoxic metabolites. J. Med. Microbiol. 47 (1998) 407-416
75. McConnell, E.L., Fadda, H.M., Basit, A.W., 2008a Gut instincts: explorations in intestinal physiology and drug delivery. Int. J. Pharm., doi:10.1016/j.ijpharm.2008.05.012.
76. McConnell E.L., Tutas J., Mohamed M.A.M., Banning D., and Basit A.W. Colonic drug delivery using amylose films: the role of aqueous ethylcellulose dispersions in controlling drug release. Cellulose 14 (2007) 25-34
77. McConnell E.L., Short M.D., and Basit A.W. An in vivo comparison of intestinal pH and bacteria as physiological trigger mechanisms for colonic targeting in man. J. Control Release 130 (2008) 154-160
78. McConnell E.L., Basit A.W., and Murdan S. Measurements of rat and mouse gastrointestinal pH, fluid and lymphoid tissue, and implications for in-vivo experiments. J. Pharm. Pharmacol. 60 (2008) 63-70
79. Meuldermans W., Hendrickx J., Mannens G., Lavrijsen K., Janssen C., Bracke J., Le Jeune L., Lauwers W., and Heykants J. The metabolism and excretion of risperidone after oral administration in rats and dogs. Drug Metab. Dispos. 22 (1994) 129-138
80. Mikov M. The metabolism of drugs by the gut flora. Eur. J. Drug Metab. Pharmacokinet. 19 (1994) 201-207
81. Minekus M., Smeets-Peeters M., Bernalier A., Marol-Bonnin S., Havenaar R., Marteau P., Alric M., Fonty G., and Huis in't Veld J.H.J. A computer-controlled system to simulate conditions of the large intestine with peristaltic mixing, water absorption and absorption of fermentation products. Appl. Microbiol. Biotechnol. 53 (1999) 108-114
82. Molly K., Vande Woestyne M., De Smet I., and Verstraete W. Validation of the simulator of the human intestinal microbial ecosystem (shime) reactor using microorganism-associated activities. Microb. Ecol. Health Dis. 7 (1994) 191-200
83. Molly K., Vande Woestyne M., and Verstraete W. Development of a 5-step multi-chamber reactor as a simulation of the human intestinal microbial ecosystem. Appl. Microbiol. Biotechnol. 39 (1993) 254-258
84. Nagengast F.M., Grubben M.J., and van Munster I.P. Role of bile acids in colorectal carcinogenesis. Eur. J. Cancer 31A (1995) 1067-1070
85. Nakayama H., Kinouchi T., Kataoka K., Akimoto S., Matsuda Y., and Ohnishi Y. Intestinal anaerobic bacteria hydrolyse sorivudine, producing the high blood concentration of 5-(e)-(2-bromovinyl)uracil that increases the level and toxicity of 5-fluorouracil. Pharmacogenetics 7 (1997) 35-43
86. Narushima S., Itoha K., Miyamoto Y., Park S.H., Nagata K., Kuruma K., and Uchida K. Deoxycholic acid formation in gnotobiotic mice associated with human intestinal bacteria. Lipids 41 (2006) 835-843
87. Nicholson J.K., and Wilson I.D. Gut microorganisms, mammalian metabolism and personalized health care. Nat. Rev. Microbiol. 3 (2005) 431-438
88. Oktyabrsky O.N., and Smirnova G.V. Dynamics of redox potential in bacterial cultures growing on media containing different sources of carbon, energy and nitrogen. Acta Biotechnol. 9 (1989) 203-209
89. Okuda H., Ogura K., Kato A., Takubo H., and Watabe T. A possible mechanism of eighteen patient deaths caused by interactions of sorivudine, a new antiviral drug, with oral 5-fluorouracil prodrugs. J. Pharmacol. Exp. Ther. 287 (1998) 791-799
90. Orme M.L.E., and Back D.J. Factors affecting the enterohepatic circulation of oral contraceptive steroids. Am. J. Obstet. Gynecol. 163 (1990) 2146-2152
91. Peppercorn M.A., and Goldman P. The role of intestinal bacteria in the metabolism of salicylazosulfapyridine. J. Pharmacol. Exp. Ther. 181 (1972) 555-562
92. Peppercorn M.A., and Goldman P. Distribution studies of salicylazosulfapyridine and its metabolites. Gastroenterology 64 (1973) 240-245
93. Peppercorn M.A., and Goldman P. Drug-bacteria interactions. Rev. Drug Inter. II (1976) 75-88
94. Possemiers S., Verthe K., Uyttendaele S., and Verstraete W. Pcr-dgge-based quantification of stability of the microbial community in a simulator of the human intestinal microbial ecosystem. FEMS Microbiol. Ecol. 49 (2004) 495-507
95. Poth E.J., Knotts F.L., Lee J.T., and Inui F. Bacteriostatic properties of sulfanilamide and some of its derivatives. Arch. Surg. 44 (1942) 187-207
96. Priebe M.G., Vonk R.J., Sun X., He T., Harmsen H.J.M., and Welling G.W. The physiology of colonic metabolism. Possibilities for interventions with pre- and probiotics. Eur. J. Nutr. 41 (2002) 102-110
97. Rafii F., Hotchkiss C., Heinze T.M., and Park M. Metabolism of daidzein by intestinal bacteria from rhesus monkeys (macaca mulatta). Comparat. Med. 54 (2004) 165-169
98. Rafii F., Sutherland J.B., Hansen E.B., and Cerniglia C.E. Reduction of nitrazepam by clostridium leptum, a nitroreductase-producing bacterium isolated from the human intestinal tract. Clin. Infect. Dis. 25 (1997) S121-S122
99. Rajilic-Stojanovic M., Smidt H., and de Vos W.M. Diversity of the human gastrointestinal tract microbiota revisited. Environ. Microbiol. 9 (2007) 2125-2136
100. Rowland I.R., Mallett A.K., Bearne C.A., and Farthing M.J.G. Enzyme activities of the hindgut microflora of laboratory animals and man. Xenobiotica 16 (1986) 519-523
101. Rubinstein A. Colonic drug delivery. Drug Discov. Today: Technol. 2 (2005) 33-37
102. Rumney C.J., and Rowland I.R. In vivo and in vitro models of the human colonic flora. Crit. Rev. Food Sci. Nutr. 31 (1992) 299-331
103. Sasaki I., Tamura T., Shibakawa T., Fujita T., Murakami M., Yamamoto A., and Muranishi S. Metabolism of azetirelin, a new thyrotropin-releasing hormone (trh) analogue, by intestinal microorganisms. Pharm. Res. 14 (1997) 1004-1007
104. Savage D.C. Microbial biota of the human intestine: A tribute to some pioneering scientists. Curr. Issues Intest. Microbiol. 2 (2001) 1-15
105. Scheline R.R. Metabolism of foreign compounds by gastrointestinal microorganisms. Pharmacol. Rev. 25 (1973) 451-523
106. Schiller L.R. Evaluation of small bowel bacterial overgrowth. Curr. Gastroenterol. Rep. 9 (2007) 373-377
107. Schneider H., Simmering R., Hartmann L., Pforte H., and Blaut M. Degradation of quercetin-3-glucoside in gnotobiotic rats, associated with human intestinal bacteria. J. Appl. Microbiol. 89 (2000) 1027-1037
108. Schröder H., and Campbell D.E.S. Absorption, metabolism, and excretion of salicylazosulfapyridine in man. Clin. Pharmacol. Ther. 13 (1972) 539-551
109. Shu Y.Z., Kingston D.G.I., Van Tassell R.L., and Wilkins T.D. Metabolism of levamisole, an anti-colon cancer drug, by human intestinal bacteria. Xenobiotica 21 (1991) 737-750
110. Siew L.F., Man S.M., Newton J.M., and Basit A.W. Amylose formulations for drug delivery to the colon: a comparison of two fermentation models to assess colonic targeting performance in vitro. Int. J. Pharm. 273 (2004) 129-134
111. Simon G.L., and Gorbach S.L. Intestinal flora in health and disease. Gastroenterology 86 (1984) 174-193
112. Sirotek K., Slovákova L., Kopečný J., and Marounek M. Fermentation of pectin and glucose, and activity of pectin-degrading enzymes in the rabbit caecal bacterium bacteroides caccae. Lett. Appl. Microbiol. 38 (2004) 327-332
113. Smith G.E., and Griffiths L.A. Metabolism of n-acetylated and o-alkylated drugs by the intestinal microflora during anaerobic incubation in vitro. Xenobiotica 4 (1974) 477-487
114. Smith H.W. Observations on the flora of the alimentary tract of animals and factorsaffecting its composition. J. Pathol. Bacteriol. 89 (1965) 95-122
115. Smith R.V. Metabolism of drugs and other foreign compounds by intestinal microorganisms. World Rev. Nutr. Diet. 29 (1978) 60-76
116. Stirrup V., Ledingham S.J., Thomas M., Pye G., and Evans D.F. Redox potential measurement in the gastrointestinal tract in man. Gut 31 (1990) A1171
117. Strong H.A., Renwick A.G., George C.F., Liu Y.F., and Hill M.J. The reduction of sulphinpyrazone and sulindac by intestinal bacteria. Xenobiotica 17 (1987) 685-696
118. Svartz N. Sulfasalazine: II. Some notes on the discovery and development of salazopyrin. Am. J. Gastroenterol. 83 (1988) 497-503
119. Takeno S., Hirano Y., Kitamura A., and Sakai T. Comparative development toxicity and metabolism of nitrazepam in rats and mice. Toxicol. Appl. Pharmacol. 121 (1993) 233-238
120. Takeno S., and Sakai T. The role of gut flora metabolism in nitrazepam-induced teratogenicity in rats. Eur. J. Pharmacol. 183 (1990) 2439-2440
121. Tannock G.W. Analysis of the intestinal microflora: a renaissance. Antonie Van Leeuwenhoek 76 (1999) 265-278
122. Thomas L.A., Veysey M.J., French G., Hylemon P.B., and Dowling R.H. Bile acid metabolism by fresh human colonic contents: a comparison of caecal versus faecal samples. Gut 49 (2001) 835-842
123. Tiwari S.B., and Rajabi-Siahboomi A.R. Extended-release oral drug delivery technologies: monolithic matrix systems. Methods Mol. Biol. 437 (2008) 217-243
124. Tozaki H., Emi Y., Horisaka E., Fujita T., Yamamoto A., and Muranishi S. Metabolism of peptide drugs by the microorganisms in rat cecal contents. Biol. Pharm. Bull. 18 (1995) 929-931
125. Tozaki H., Emi Y., Horisaka E., Fujita T., Yamamoto A., and Muranishi S. Degradation of insulin and calcitonin and their protection by various protease inhibitors in rat caecal contents: implications in peptide delivery to the colon. J. Pharm. Pharmacol. 49 (1997) 164-168
126. Tuleu C., Basit A.W., Waddington W.A., Ell P.J., and Newton J.M. Colonic delivery of 4-aminosalicylic acid using amylose-ethylcellulose-coated hydroxypropylmethylcellulose capsules. Aliment. Pharmacol. Ther. 16 (2002) 1771-1779
127. Van Hogezand R.A., Kennis H.M., Van Schaik A., Koopman J.P., and van Hees P.A.M. Bacterial acetylation of 5-aminosalicylic acid in faecal suspensions cultured under aerobic and anaerobic conditions. Eur. J. Clin. Pharmacol. 43 (1992) 189-192
128. Varum F.J., McConnell E.L., Sousa J.J., Veiga F., and Basit A.W. Mucoadhesion and the gastrointestinal tract. Crit. Rev. Ther. Drug Carrier Syst. 25 (2008) 207-258
129. Vaughan E.E., Schut F., Heilig H.G., Zoetendal E.G., de Vos W.M., and Akkermans A.D. A molecular view of the intestinal ecosystem. Curr. Issues Intest. Microbiol. 1 (2000) 1-12
130. Vermes A., Kuijper E.J., Guchelaar H.J., and Dankert J. An in vitro study on the active conversion of flucytosine to fluorouracil by microorganisms in the human intestinal microflora. Chemotherapy 49 (2003) 17-23
131. Wadworth A.N., and Fitton A. Olsalazine-a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in inflammatory bowel disease. Drugs 41 (1991) 647-664
132. Wang M., Ahrne S., Jeppsson B., and Molin G. Comparison of bacterial diversity along the human intestinal tract by direct cloning and sequencing of 16S rRNA genes. FEMS Microbiol. Ecol. 54 (2005) 219-231
133. Watanabe K., Yamashita S., Furuno K., Kawasaki H., and Gomita Y. Metabolism of omeprazole by gut flora in rats. J. Pharm. Sci. 84 (1995) 516-517
134. Whitman W.B., Coleman D.C., and Wiebe W.J. Prokaryotes: the unseen majority. Proc. Natl. Acad. Sci. U.S.A. 95 (1998) 6578-6583
135. Wilding I.R. The enterion capsule: a novel technology for undersanding the biopharmaceutical complexicity of new molecular entities (NMEs). Drug Del. Technol. 1 (2001) 8-11
136. Williams B.A., Bosch M.W., Awati A., Konstantinov S.R., Smidt H., Akkermans A.D.L., Verstegen M.W.A., and Tamminga S. In vitro assessment of gastrointestinal tract (git) fermentation in pigs: fermentable substrates and microbial activity. Anim. Res. 54 (2005) 191-201
137. Wilson P.J., and Basit A.W. Exploiting gastrointestinal bacteria to target drugs to the colon: an in vitro study using amylose coated tablets. Int. J. Pharm. 300 (2005) 89-94
138. Winter J., and Bokkenheuser V.D. Bacterial metabolism of natural and synthetic sex hormones undergoing enterohepatic circulation. J. Steroid Biochem. 27 (1987) 1149-1154
139. Yang L. Biorelevant dissolution testing of colon-specific delivery systems activated by colonic microflora. J. Control Release 125 (2008) 77-86
140. Yoshisue K., Masuda H., Matsushima E., Ikeda K., Nagayama S., and Kawaguchi Y. Tissue distribution and biotransformation of potassium oxonate after oral administration of a novel antitumor agent (drug combination of tegafur, 5-chloro-2,4-dihydroxypyridine, and potassium oxonate) to rats. Drug Metab. Dispos. 28 (2000) 1162-1167