Intraluminal pH in Ulcerative Colitis
Alan V Safdi, MD
Volume 6, January 19, 2012
Intraluminal pH varies along the length of the digestive tract in a relatively predictable pattern. In healthy individuals, there is a progressive increase from the duodenum to the terminal ileum, a decrease in the cecum, and then a slow increase along the colon to the rectum. In patients with ulcerative colitis (UC), a similar but somewhat more acidic pattern is sometimes observed. Colonic pH during a UC flare can be extremely low, secondary to the accumulation of short-chain fatty acids (pKa = 4.8) and lactic acid. Several of the mesalamine formulations available for UC treatment incorporate a pH-dependent coating that is designed to prevent release of the active drug in the upper gastrointestinal tract and subsequently target release in the colon.
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Early studies of intraluminal pH depended on aspiration of gastric or intestinal fluids or measurements on stool.1,2 More recently, a number of studies have directly measured pH in the digestive tract. Methodologies include the use of radiotelemetry capsules, tube-mounted pH electrodes, and endoscopic placement of pH-sensitive electrodes.1 Radiotelemetry capsules are ingested orally and consist of 2 electrodes that take from 1 to 5 days to pass through the gastrointestinal tract. One electrode serves as a reference, and the other is pH sensitive and transmits measurements from the gut lumen to a recorder via an antenna. Tube-mounted pH electrodes consist of a catheter with several electrodes positioned at specific intervals along its length. The catheter is passed orally through the stomach and small intestine and into the colon using fluoroscopy, and pH measurements are recorded and stored on an external unit. As an alternative to passing electrodes through the gastrointestinal tract, pH-sensitive electrodes can also be endoscopically placed on the luminal surface of the colonic mucosa; however, this method cannot be used in the small intestine or to measure pH over long time periods.1 More recently, the "Smart Pill" has made these measurements easier to perform.
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Radiotelemetry capsules have most often been used to study intraluminal pH in healthy individuals. In a review of 9 such studies (N=167), Nugent et al1 report that pH in the lumen of the small intestine increases from 5.5 to 7.0 proximally to 6.5 to 7.5 in the distal ileum. Then, in the cecum, intraluminal pH decreases (range=5.5-7.5) and rises again in the left colon and rectum (range=6.1-7.5). There is some debate about where the decrease in pH between the distal ileum and the cecum actually begins. Fallingborg et al3 studied the pH profile of 39 healthy individuals and found that, although there was a sharp decrease in pH when the radiotelemetry capsule entered the cecum, 17 individuals experienced a decrease between 0.1 and 0.8 pH units while the capsule was still in the distal small intestine (Figure). The same study also reported that, in healthy individuals, median pH values were always less than 7.0 in the cecum, ascending colon, transverse colon, and descending colon. Furthermore, Fallingborg et al3 reported that as many as 25% of healthy individuals do not reach a pH of 7.0 anywhere along their gastrointestinal tract.
The rise in intraluminal pH between the stomach and the small intestine is most likely the result of alkaline pancreatic secretions and mucosal bicarbonate secretion in the terminal ileum. The subsequent decrease in pH in the cecum is probably due to the generation of short-chain fatty acids as colonic bacteria ferment carbohydrates. Then, pH again rises in the distal colon as short-chain fatty acids are absorbed and metabolized by the colonic epithelium in exchange with mucosal bicarbonate secretion.1
Figure. pH levels vary in healthy volunteers—percentile of all pH values by intraluminal location of capsule (N=39). Sto=Stomach; Duo=duodenum; Pro=proximal small intestine; Mid=Mid small intestine; Dis=Distal small intestine; Cec=cecum; Asc=ascending colon; Tra=transverse colon; Des=descending colon; R/S=rectum or sigmoid colon; Fec=feces. Adapted with permission from Fallingborg et al.3 Aliment Pharmacol Ther. 1989;3:605-613. ©1989 Wiley-Blackwell.
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There are fewer studies of intraluminal pH in patients with UC. Fallingborg et al4 obtained measurements from 6 patients with very active UC and found that, while pH levels in the stomach and small intestine were within the normal range, the intraluminal pH of the 3 patients with the most severe disease decreased to 2.4 to 3.4 in the right colon (the other 2 patients had colonic pH that was almost neutral). A study by Press et al5 included 7 patients with active UC and 4 patients with inactive UC. The investigators found that pH ranged from 7.75 to 9.2 in the terminal ileum, 6.3 to 7.4 in the cecum, and 6.3 to 7.8 in the right colon. A study by Ewe et al6 included 5 patients with UC (1 moderate and 4 severe) and found that median pH was approximately 6.9 in the terminal ileum, 5.5 in the cecum, and 7.3 in the right colon.
More recently, Rubin et al7,8 used "Smart Pill" technology to publish 2 abstracts focusing on colonic pH in patients with UC. In 1 of the abstracts, the investigators followed 2 patients with mildly to moderately active UC to study the relationship between disease activity and pH.7 Both patients experienced a substantial increase in colonic pH when they achieved clinical remission. For example, in patient 1, pH in the proximal colon increased from 6.22 to 6.82, and pH in the distal colon increased from 6.84 to 9.77. In patient 2, pH in the proximal colon increased from 5.44 to 7.36, and pH in the distal colon increased from 5.3 to 7.73. In the other abstract, Rubin et al8 again studied the relationship between disease activity and pH by measuring pH levels in 8 patients in clinical remission. The investigators reported that the colonic pH of the 8 patients was similar to the values reported in healthy individuals. These data may be important to consider when using a mucosally active drug that has a pH-dependent delivery system.
A number of factors, including decreased mucosal bicarbonate secretion, increased mucosal and bacterial lactate production, impaired short-chain fatty acid absorption and metabolism, changes in intestinal transit time, and reduced dietary fiber intake, are hypothesized to contribute to the decreased colonic pH observed in patients with active UC.1,5 However, the limited number of individuals included in each of the above studies, as well as differences in disease severity and diet among individuals, makes it difficult to generalize about the typical luminal pH profile of patients with UC.
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Aminosalicylates (5-ASAs), like mesalamine, sulfasalizine, olsalazine, and balsalazide, are typically considered first-line therapy for inducing or maintaining remission in mild to moderate UC.9 Although their exact mechanism of action is unclear, 5-ASAs appear to have a direct, anti-inflammatory effect on the colonic mucosa.10 They are thought to inhibit the cyclooxygenase and lipoxygenase pathways. Therefore, their efficacy is dependent on the drug reaching the colon before it is degraded and absorbed in the small intestine. The ideal drug results in a high mucosal 5-ASA concentration, with low serum 5-ASA concentrations, high stool N-acetyl-5-ASA concentrations, and low stool 5-ASA concentrations. To take advantage of the pH profile of the gastrointestinal tract, some mesalamine formulations include a pH-sensitive enteric polymer coating that does not dissolve and permit release of the active drug until the luminal pH increases above a critical value (ideally, the pH of the colon).11 This limits mesalamine absorption in the small intestine (which has no known therapeutic benefit and can cause systemic side effects) and promotes maximum delivery to the colon, where the drug's clinical efficacy is directly correlated with its concentration in the mucosa.12 There are 3 common pH-dependent mesalamine delivery systems used in the United States.11 Two incorporate a Eudragit®-S (Evonik Industries) resin that dissolves at either pH ≥7.0 (Asacol®; Warner Chilcott Company, LLC) or ≥6.8 (Lialda®; Shire LLC). The third (APRISO™; Salix Pharmaceuticals, Inc) incorporates a Eudragit®-L resin that is designed to dissolve at pH ≥6.0. The table provides an overview of the 3 different pH-dependent mesalamine formulations currently available.
Due to the high interpatient variability in gastrointestinal pH and potentially very low colonic pH in patients with UC, not all patients will benefit from a pH-dependent mesalamine delivery system. Some may instead find that a 5-ASA like balsalazide is more effective, since it works independently of pH levels. Balsalazide is an azo-bonded prodrug that releases 5-ASA when it comes into contact with colonic bacteria. In a recent study, balsalazide effectively induced remission in patients with UC who had not responded to a pH 7–dependent mesalamine.13 The study hypothesized that pH 7–dependent 5-ASAs may not be effective in certain individuals because of increased fecal wasting of the drug.
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Although a number of UC drugs incorporate mesalamine as their active component, drug release is variable among patients with UC. Consideration of gastrointestinal pH may be helpful in choosing the appropriate drug. Balsalazide, which works independently of pH, is another 5-ASA option that has demonstrated effectiveness in comparative efficacy studies.14,15
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| About the author |
 |  Alan V Safdi, MD Dr Safdi is President and cofounder of Consultants for Clinical Research, a multispecialty research facility involved in clinical research evaluating new investigational and existing medications, as well as medical devices. He is currently the principal investigator for a variety of studies and has published numerous articles in peer-reviewed publications, including the American Journal of Medicine, the American Journal of Gastroenterology, the Annals of Internal Medicine, and a variety of other prominent medical journals. Dr Safdi also serves as President of the Ohio Gastroenterology and Liver Institute, Vice President and Secretary of the Ohio Gastroenterology Society, and Medical Director of the Tri-State Endoscopy Centers. In the past, he has served as the President, Treasurer, and Secretary for the Southwest Ohio Digestive Disease Society, as well as the Chairman of the Cincinnati Crohn's and Colitis Medical Advisory Committee. |
| About the author |
|  Alan V Safdi, MD Dr Safdi is President and cofounder of Consultants for Clinical Research, a multispecialty research facility involved in clinical research evaluating new investigational and existing medications, as well as medical devices. He is currently the principal investigator for a variety of studies and has published numerous articles in peer-reviewed publications, including the American Journal of Medicine, the American Journal of Gastroenterology, the Annals of Internal Medicine, and a variety of other prominent medical journals. Dr Safdi also serves as President of the Ohio Gastroenterology and Liver Institute, Vice President and Secretary of the Ohio Gastroenterology Society, and Medical Director of the Tri-State Endoscopy Centers. In the past, he has served as the President, Treasurer, and Secretary for the Southwest Ohio Digestive Disease Society, as well as the Chairman of the Cincinnati Crohn's and Colitis Medical Advisory Committee. |
| About the author |
|  Alan V Safdi, MD Dr Safdi is President and cofounder of Consultants for Clinical Research, a multispecialty research facility involved in clinical research evaluating new investigational and existing medications, as well as medical devices. He is currently the principal investigator for a variety of studies and has published numerous articles in peer-reviewed publications, including the American Journal of Medicine, the American Journal of Gastroenterology, the Annals of Internal Medicine, and a variety of other prominent medical journals. Dr Safdi also serves as President of the Ohio Gastroenterology and Liver Institute, Vice President and Secretary of the Ohio Gastroenterology Society, and Medical Director of the Tri-State Endoscopy Centers. In the past, he has served as the President, Treasurer, and Secretary for the Southwest Ohio Digestive Disease Society, as well as the Chairman of the Cincinnati Crohn's and Colitis Medical Advisory Committee. |
Important Safety Information about APRISO
APRISO is a locally acting aminosalicylate indicated for the maintenance of remission of ulcerative colitis in patients 18 years and older. APRISO is contraindicated in patients with hypersensitivity to salicylates or aminosalicylates (sulfasalazine) or to any of the components of APRISO capsules. It is recommended that patients have an evaluation of renal function prior to initiation of APRISO therapy and periodically while on therapy. Exercise caution when using APRISO in patients with known renal dysfunction or a history of renal disease. Mesalamine has been associated with an acute intolerance syndrome that may be difficult to distinguish from a flare of inflammatory bowel disease. Symptoms include cramping, acute abdominal pain and bloody diarrhea, sometimes fever, headache, and rash. If acute intolerance syndrome is suspected, promptly discontinue treatment with APRISO. There have been reports of hepatic failure in patients with pre-existing liver disease who have been administered mesalamine. Caution should be exercised when administering APRISO to patients with liver disease. The recommended dose of APRISO is four 0.375-g capsules once daily in the morning (1.5 g/day) with or without food. Because dissolution of the coating of APRISO granules depends on pH, APRISO should not be coadministered with antacids. Patients with phenylketonuria should be aware that APRISO contains aspartame, equivalent to 2.24 mg of phenylalanine per day. In 2 well-controlled clinical trials, the most common treatment-related adverse events occurring in at least 3% of adult patients taking 1.5 g/day of APRISO and at a rate greater than placebo were headache (11% vs 8% for placebo), diarrhea (8% vs 7% for placebo), upper abdominal pain (5% vs 3% for placebo), nausea (4% vs 3% for placebo), nasopharyngitis (4% vs 3% for placebo), influenza and influenza-like illness (4% vs 4% for placebo), and sinusitis (3% vs 3% for placebo).
For complete Prescribing Information
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1. Nugent SG, Kumar D, Rampton DS, Evans DF. Intestinal luminal pH in inflammatory bowel disease: possible determinants and implications for therapy with aminosalicylates and other drugs. Gut. 2001;48:571-577. 2. Fallingborg J. Intraluminal pH of the human gastrointestinal tract. Dan Med Bull. 1999;46:183-196. 3. Fallingborg J, Christensen LA, Ingeman-Nielsen M, Jacobsen BA, Abildgaard K, Rasmussen HH. pH-profile and regional transit times of the normal gut measured by a radiotelemetry device. Aliment Pharmacol Ther. 1989;3:605-613. 4. Fallingborg J, Christensen LA, Jacobsen BA, Rasmussen SN. Very low intraluminal colonic pH in patients with active ulcerative colitis. Dig Dis Sci. 1993;38:1989-1993. 5. Press AG, Hauptmann IA, Hauptmann L, et al. Gastrointestinal pH profiles in patients with inflammatory bowel disease. Aliment Pharmacol Ther. 1998;12:673-678. 6. Ewe K, Schwartz S, Petersen S, Press AG. Inflammation does not decrease intraluminal pH in chronic inflammatory bowel disease. Dig Dis Sci. 1999;44:1434-1439. 7. Rubin D, Gavzy S, Chapman C, et al. Colonic pH differs depending on the activity of ulcerative colitis (UC): Report of two patients with pH measurements over time. Presentation at the 74th American College of Gastroenterology Annual Scientific Meeting; October 23-28, 2009; San Diego, CA: Abstract 1224. 8. Rubin DT, Bunnag AP, Surma BL, et al. Measurement of luminal pH in patients with mildly to moderately active UC: Pilot study using SmartPill pH. Gastroenterology. 2009;136(suppl 1):M1097. 9. Carter MJ, Lobo AJ, Travis SP; IBD Section, British Society of Gastroenterology. Guidelines for the management of inflammatory bowel disease in adults. Gut. 2004;53 (suppl 5):V1-V16. 10. Oliveira L, Cohen RD. Maintaining remission in ulcerative colitis—role of once daily extended-release mesalamine. Drug Des Devel Ther. 2011;5:111-116. 11. Lichtenstein GR. Mesalamine in the treatment of ulcerative colitis: Novel therapeutic options. Gastroenterol Hepatol. 2009;5:65-73. 12. Wilding IR, Behrens C, Tardif SJ, Wray H, Bias P, Albrecht W. Combined scintigraphic and pharmacokinetic investigation of enteric-coated mesalazine micropellets in healthy subjects. Aliment Pharmacol Ther. 2003;17:1153-1162. 13. Safdi A. The effect of high-dose balsalazide on the modified Sutherland ulcerative colitis activity index in patients with UC. Presentation at the 74th American College of Gastroenterology Annual Scientific Meeting; October 23-28, 2009; San Diego, CA. Abstract 1172. 14. Green JR, Lobo AJ, Holdsworth CD, et al. Balsalazide is more effective and better tolerated than mesalamine in the treatment of acute ulcerative colitis. The Abacus Investigator Group. Gastroenterology. 1998;114:15-22. 15. Pruitt R, Hanson J, Safdi M, et al. Balsalazide is superior to mesalamine in the time to improvement of signs and symptoms of acute mild-to-moderate ulcerative colitis. Am J Gastroenterol. 2002;97:3078-3086.