Advertisement

Clinical Pharmacokinetics

, Volume 2, Issue 1, pp 45–60 | Cite as

Drug Absorption in Gastrointestinal Disease With Particular Reference to Malabsorption Syndromes

  • R. L. Parsons
Article

Summary

There is a considerable range in the dose of many drugs that is required to produce a given pharmacological effect in an individual patient. This individual variation in dose requirement is sometimes reflected in the wide scatter in the steady state plasma concentration that follows the same oral dose of a drug given to any group of subjects. Such individual differences are largely due to variation in the rate of elimination of drugs.

Gastrointestinal disease may also alter oral dose requirements by producing variation in both the amount and rate of drug absorption. These changes may be reflected in the plasma concentration/time curve that follows an oral dose.

The amount of drug absorbed is simultaneously affected by many factors. These include the physicochemical properties of the drug and the physiological factors that operate within the gut, as well as the presence of other substances such as food, or interaction with other drugs in the gut. The availability of the drug within the intestinal lumen is largely governed by its dissolution characteristics, particularly factors which can interfere with dissolution of the drug product in the gut.

Physiological factors within the gut that affect oral drug absorption include gastric emptying rate and intestinal motility, the pH of the gastrointestinal fluids, the activity of gastrointestinal drug metabolising enzymes (e.g. monoamine oxidase and dopa decarboxylase) or drug metabolising bacteria and the surface area of the gut.

Many factors affect gastric emptying. These include disease, surgery and other drugs. A change in the rate of gastric emptying alters the rate of drug delivery from the stomach to the duodenum and upper small intestine. This may profoundly alter the plasma concentration/time curve that follows oral administration of many drugs.

For some drugs, proximal jejunal disease may reduce, delay or increase the apparent amount of drug absorbed. Reduced absorption of an antibiotic leads to a fall in the peak plasma concentration. If the peak falls below the minimum inhibitory concentration for a particular organism then therapeutic failure may occur, if it is assumed that the peak plasma concentration is all important for antimicrobial activity. Excessive drug absorption may lead to drug toxicity.

Abnormal drug absorption is a feature of lower small intestinal conditions such as Crohn’s disease. This suggests that drug absorption is not confined to the jejunum but continues throughout the small intestine.

It is not always possible to predict the pattern of drug malabsorption from a knowledge of the physicochemical and pharmacokinetic properties of the drug and the pathophysiology of the disease. The rate and amount of drug absorbed by one patient may differ from that in another patient with the same condition. Although these differences reflect normal individual variation, they are also related to the extent and activity of disease at the time of study.

The similar abnormal plasma concentration/time curve that follows oral administration of clindamycin, sulphamethoxazole and trimethoprim in coeliac disease, small bowel diverticulosis and Crohn’s disease suggests that a similar underlying mechanism in these conditions is responsible for the abnormal absorption of these three physicochemically unrelated drugs.

Keywords

Digoxin Gastric Emptying Metoclopramide Peak Plasma Concentration Coeliac Disease 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Alexander, J.O’D.; Young, E.; McFadyen, T.; Fraser, N.G.; Duguid, W.P. and Meredith, E.M.: Absorption and excretion of 35S Dapsone in dermatitis herpetiformis. British Journal of Dermatology 83: 620–631 (1970).PubMedCrossRefGoogle Scholar
  2. Anthonisen, P.; Barany, F.; Folkenborg, O.; Holtz, A.; Jarnum, S.; Kristensen, M.; Riis, P.; Walan, A. and Worning, H.: The clinical effect of salazosulfapyridine (Salazopyrin) in Crohn’s disease. A controlled double-blind study. Scandinavian Journal of Gastroenterology 9: 549–554 (1974).PubMedGoogle Scholar
  3. Antonioli, J.A.; Schelling, J.L.; Steininger, E. and Borel, G.A.: Effect of gastrectomy and of an anticholinergic drug on the gastrointestinal absorption of a sulfonamide in man. International Journal of Clinical Pharmacology 5: 212–215 (1971).Google Scholar
  4. Bank, S.; Saunders, S.J.; Marks, I.N.; Novis, B.H. and Barbezat, G.O.: Clinical pharmacological considerations in gastrointestinal and hepatic diseases; in Avery (Ed) Drug Treatment, p. 507–509 (ADIS Press, Sydney; Publishing Sciences Group, Acton; Churchill Livingstone, Edinburgh 1976).Google Scholar
  5. Baron, J.H. and Lennard-Jones, J.E.: Gastric secretion in health and disease. British Journal of Hospital Medicine 6: 303–306 (1971).Google Scholar
  6. Beerman, B.; Hellstrom, K. and Rosen, A.: The gastrointestinal absorption of digoxin in 7 patients with gastric or small intestinal reconstructions. Acta Medica Scandinavica 193: 293–297 (1973).CrossRefGoogle Scholar
  7. Benn, A. and Cooke, W.T.: Intraluminal pH of duodenum and jejunum in fasting subjects with normal and abnormal gastric or pancreatic function. Scandinavian Journal of Gastroenterology 6: 313–317 (1971).PubMedCrossRefGoogle Scholar
  8. Bromster, D.: Gastric emptying rate in gastric and duodenal ulceration. A clinical study including the changes of the gastric contents after a liquid test meal. Scandinavian Journal of Gastroenterology 4: 193–201 (1969).PubMedCrossRefGoogle Scholar
  9. Bushby, S.R.M. and Hitchings, G.H.: Trimethoprim, a sulphonamide potentiator. British Journal of Pharmacology and Chemotherapy 33: 72–90 (1968).PubMedGoogle Scholar
  10. Casteels van Daele, M.; Jaecken, J.; Van der Schueren, P.; Zimmerman, A. and Van den Bon, P.: Dystonic reactions in children caused by metaclopramide. Archives of Diseases of Childhood 45: 130–133 (1970).CrossRefGoogle Scholar
  11. Chanarin, I. and England, J.M.: Toxicity of trimethoprim-sulphamethoxazole in patients with megaloblastic haemopoiesis. British Medical Journal 1: 651–653 (1972).PubMedCrossRefGoogle Scholar
  12. Chisholm, G.D.; Waterworth, P.M.; Calnan, J.S. and Garrod, L.P.: Concentration of antibacterial agents in interstitial tissue fluid. British Medical Journal 1: 569–573 (1973).PubMedCrossRefGoogle Scholar
  13. Consolo, S.; Morselli, P.L.; Laccala, M. and Garanttini, S.: Delayed absorption caused by desmethylimipramine in humans. European Journal of Pharmacology 10: 239–242 (1970).PubMedCrossRefGoogle Scholar
  14. Crammer, J.L.; Rosser, R.M. and Crance, G.: Blood levels and management of lithium treatment. British Medical Journal 3: 650–654 (1974).PubMedCrossRefGoogle Scholar
  15. Das, K.M. and Dubin, R.: Clinical pharmacokinetics of sulfasalazine. Clinical Pharmacokinetics 1: 406–425 (1976).PubMedCrossRefGoogle Scholar
  16. Davies, J.A.; Strangeways, J.E.M. and Holt, J.M.: Absorption of cephalexin from the gastrointestinal tract in diseased subjects. Postgraduate Medical Journal 46 (Suppl.): 16–19 (Oct 1970).CrossRefGoogle Scholar
  17. Davies, J.A.: Absorption of cephalexin in diseased and aged subjects. Journal of Antimicrobial Chemotherapy 1 (Suppl.): 69–70 (1975).PubMedCrossRefGoogle Scholar
  18. De Silva, K.L.; Muller, P.J. and Pearce, J.: Acute drug-induced extrapyramidal syndromes. Practitioner 211: 316–320 (1973).PubMedGoogle Scholar
  19. Dordoni, B.; Willson, R.A.; Thompson, R.P.H. and Williams, R.: Reduction of absorption of paracetamol by activated charcoal and cholestyramine: a possible therapeutic measure. British Medical 1 3: 86–87 (1973).CrossRefGoogle Scholar
  20. Eisborg, L.: Malabsorption of folic acid following partial gastrectomy. Scandinavian Journal of Gastroenterology 9: 271–274 (1974).Google Scholar
  21. Gallo, D.G.; Bailey, K.R. and Sheffner, A.L.: The interaction between cholestyramine and drugs. Proceedings of the Society of Experimental Biology and Medicine 120: 60–65 (1965).Google Scholar
  22. Goldman, P.; Peppercorn, M.A. and Goldin, B.R.: Drugs metabolised by intestinal microflora; in Morselli, Cohen and Garattini (Eds) Drug Interactions, p.91 (Raven Press, New York 1974).Google Scholar
  23. Gothoni, G.; Pentikainen, P.; Vapaatalo, H.I.; Hackman, R. and Bjorksten, K.: Absorption of antibiotics: influence of metoclopramide and atropine on serum levels of pivampicillin and tetracycline. Annals of Clinical Research 4: 228–232 (1972).PubMedGoogle Scholar
  24. Halvorsen, L.; Doterall, G. and Walan, A.: Gastric emptying in patients with achlorhydria or hyposecretion of hydrochloric acid. Scandinavian Journal of Gastroenterology 8: 395–399 (1973).PubMedGoogle Scholar
  25. Harris, F.C.: Pyloric stenosis. Hold-up of enteric coated aspirin tablets. British Journal of Surgery 60: 979–981 (1973).PubMedCrossRefGoogle Scholar
  26. Hayes, A. and Cooper, R.G.: Studies on the absorption, distribution and excretion of propranolol in rat, dog and monkey. Journal of Pharmacology and Experimental Therapeutics 176: 302–311 (1971).PubMedGoogle Scholar
  27. Heizer, W.D.; Smith, T.W. and Goldfinger, S.E.: Absorption of digoxin in patients with malabsorption syndromes. New England Journal of Medicine 285: 257–259 (1971).PubMedCrossRefGoogle Scholar
  28. Howarth, F.H.; Cockel, R.; Roper, B.W. and Hawkins, C.F.: The effect of metoclopramide upon gastric motility and its value in barium progress meals. Clinical Radiology 20: 294–300 (1969).PubMedCrossRefGoogle Scholar
  29. Hurwitz, A. and Schlozman, D.L.: Effects of antacids on gastrointestinal absorption of isoniazid in rat and man. American Review of Respiratory Diseases 179: 124–131 (1974).Google Scholar
  30. James, I.M.: Disease and adverse drug reactions. Adverse Drug Reaction Bulletin No. 51 (April 1975).Google Scholar
  31. James, W.B. and Hume, R.: Action of metoclopramide on gastric emptying and small bowel transit time. Gut 9: 203–205 (1968).PubMedCrossRefGoogle Scholar
  32. John, A.H. and Jones, A.: Gastroenteritis causing failure of oral contraception. British Medical Journal 3: 207–208 (1975).PubMedCrossRefGoogle Scholar
  33. Jussila, J.; Matilla, M.J. and Takki, S.: Drug absorption during lactose-induced intestinal symptoms in patients with selective lactose malabsorption. Annales Medicinae Experimentalis et Biologiae Fenniae 48: 33–37 (1970).PubMedGoogle Scholar
  34. Kaye, C.M.; Robinson, D.G. and Turner, P.: The influence of urine pH on the renal excretion of practolol and propranolol. British Journal of Pharmacology 49: 155P (1973).Google Scholar
  35. Lee, C.C. and Anderson, R.C.: Absorption, distribution and excretion of i-α-phenoxypropyl, d-α-phenoxy, dl-α-phenoxyethyl and phenoxymethyl penicillins. Antimicrobial Agents and Chemotherapy, pp.555–567 (1961).Google Scholar
  36. Lee, C.C.; Forman, R.O.; Anderson, R.C. and Chen, K.K.: Gastric and intestinal absorption of penicillin V, potassium and the free acid. Antibiotics and Chemotherapy 8: 354–360 (1958).Google Scholar
  37. Levine, R.R.: Factors affecting gastro-intestinal absorption of drugs. Amer. J. digest. Dis. 15: 171–188 (1970).CrossRefGoogle Scholar
  38. Levine, R.R. and Walsh, C.T.: Drug interactions inthe gastrointestinal tract; in Friedman (Ed) Functions of the Stomach and Intestine, p.349–373 (University Park Press, Baltimore 1975).Google Scholar
  39. Lindenbaum, J.; Maulitz, R.M. and Butler, V.P.: Inhibition of digoxin absorption by neomycin. Gastroenterology 71: 399–404 (1976).PubMedGoogle Scholar
  40. Lode, H.; Frisch, D. and Naumann, P.: Oral antibiotic therapy in patients with partial gastrectomy; in Daikos (Ed) Progress in Chemotherapy, Vol. 1, p.543–546 (Helenic Society of Chemotherapy, Athens 1974).Google Scholar
  41. Lupinsky, I. and Berthoud, S.: Absorption of penicillin V in relation to digestive disorders. Schweizerische Rundschau Medizinische (Praxis) 62: 959–963 (1973).Google Scholar
  42. Manninen, V.; Apajalahti, A.; Melin, J. and Karesoja, M.: Altered absorption of digoxin in patients given propantheline and metoclopramide. Lancet 1: 398–399 (1973a).PubMedCrossRefGoogle Scholar
  43. Manninen, V.; Apajalahti, A.; Melin, J. and Karesoja, M.: Effect of propantheline and metoclopramide on the absorption of digoxin. Lancet 1:1118–1119 (1973b)PubMedCrossRefGoogle Scholar
  44. Matilla, M.J.; Friman, A.; Larmi, T.K.I. and Koskinen, R.: Absorption of ethionamide, isoniazid, and aminosalicylic acid from the post-resection gastrointestinal tract. Annales Medicinae Experimentalis et Biologiae Fenniae 47: 209–212 (1969).Google Scholar
  45. May, J.R. and Davies, J.: Resistance of Haemophilus influenzae to trimethoprim. British Medical Journal 3: 376–377 (1972).PubMedCrossRefGoogle Scholar
  46. Mearrick, P.T.; Wade, D.N.; Birkett, D.J. and Morris, J.: Metoclopramide, gastric emptying and L-dopa absorption. Australian and New Zealand Journal of Medicine 4: 138–143 (1974).PubMedCrossRefGoogle Scholar
  47. Moberg, S. and Carlberger, G.: Gastric emptying in healthy subjects and in patients with various malabsorption states. Scandinavian Journal of Gastroenterology 9: 17–21 (1974).PubMedGoogle Scholar
  48. Morris, J.G.L.; Parsons, R.L.; Trounce, J.R. and Groves, M.J.: Plasma dopa concentrations after different preparations of levodopa in normal subjects. British Journal of Clinical Pharmacology 3: (in press, 1976).Google Scholar
  49. Nelson, E.B.; Raj, P.P.; Belfi, K.J. and Masters, B.S.S.: Oxidative drug metabolism in human liver microsomes. Journal of Pharmacology and Experimental Therap. 178: 580–588 (1971).Google Scholar
  50. Nelson, J.D.; Shelton, S.; Kusmiesz, H.T. and Haltalin, K.C.: Absorption of ampicillin and nalidixic acid by infants and children with acute shigellosis. Clinical Pharmacology and Therapeutics 13: 879–886 (1972).PubMedGoogle Scholar
  51. Nimmo, W.S.: Drugs, diseases and altered gastric emptying. Clinical Pharmacokinetics 1: 189–203 (1976).PubMedCrossRefGoogle Scholar
  52. Nimmo, J.; Heading, R.C.; Tothill, P. and Prescott, L.F.: Pharmacological modification of gastric emptying: effects of propantheline and metoclopramide on paracetamol absorption. British Medical Journal 1: 587–589 (1973).PubMedCrossRefGoogle Scholar
  53. Nimmo, W.S.; Heading, R.C.; Wilson, J.; Tothill, P. and Prescott, L.F.: Inhibition of gastric emptying and drug absorption by narcotic analgesics. British Journal of Clinical Pharmacology 2: 509–513 (1975a).PubMedCrossRefGoogle Scholar
  54. Nimmo, W.S.; Wilson, J. and Prescott, L.F.: Narcotic analgesics and delayed gastric emptying during labour. Lancet 1: 890–893 (1975b).PubMedCrossRefGoogle Scholar
  55. Parsons, R.L.; Hossack, D.J.N.; Bywater, M.J.; Humphreys, D.M. and Hailey, D.M.: The absorption of antibiotics in small bowel diverticulosis; in Daikos (Ed) Progress in Chemotherapy, Vol. 1, p.507–513 (Hellenic Society of Chemotherapy, Athens 1974).Google Scholar
  56. Parsons, R.L. and Kaye, C.M.: Plasma propranolol and practolol in adult coeliac disease. British Journal of Clinical Pharmacology 1: 348P (1974).Google Scholar
  57. Parsons, R.L.; Hossack, G.A. and Paddock, G.M.: The absorption of antibiotics in adult patients with coeliac disease. Journal of Antimicrobial Chemotherapy 1: 39–50 (1975).PubMedCrossRefGoogle Scholar
  58. Parsons, R.L.; Hossack, G.A. and Paddock, G.M.: Pharmacokinetics of pivmecillinam. British Journal of Clinical Pharmacology. In press (1977).Google Scholar
  59. Parsons, R.L. and Paddock, C.M.: Absorption of two antibacterial drugs, cephalexin and co-trimoxazole in malabsorption syndromes. Journal of Antimicrobial Chemotherapy 1 (Suppl.): 59–67 (1975).PubMedCrossRefGoogle Scholar
  60. Parsons, R.L.; Paddock, G.M. and Hossack, G.A.: Cholestyramine induced antibiotic malabsorption; in Williams and Geddes (Eds) Chemotherapy, Vol. 4, Pharmacology of Antibiotics, p. 191–198 (Plenum Press, New York 1976a).Google Scholar
  61. Parsons, R.L.; Paddock, G.M.; Hossack, G.A. and Hailey, D.M.: Antibiotic absorption in Crohn’s disease; in Williams and Geddes (Eds) Chemotherapy, Vol. 4, Pharmacology of Antibiotics, p.219–229 (Plenum Press, New York 1976b).Google Scholar
  62. Parsons, R.L.; Jusko, W.J. and Lewis, G.P.: Pharmacokinetics of antibiotic absorption in coeliac disease. Journal of Antimicrobial Chemotherapy 2: 214–215 (1976c).PubMedCrossRefGoogle Scholar
  63. Parsons, R.L.; Kaye, C.M.; Raymond, K.; Trounce, J.R. and Turner, P.: Absorption of propranolol and practolol in coeliac disease. Gut 17: 139–143 (1976d).PubMedCrossRefGoogle Scholar
  64. Paterson, J.W.; Conolly, M.E.; Dollery, C.T.; Hayes, A. and Cooper, R.G.: The pharmacodynamics and metabolism of propranolol in man. Pharmacologia Clinica 2: 127–133 (1970).CrossRefGoogle Scholar
  65. Plotkin, G.R. and Isselbacher, K.J.: Secondary disaccharidase deficiency in adult celiac disease (non-tropical sprue) and other malabsorption states. New England Journal of Medicine 271: 1033–1037 (1964).PubMedCrossRefGoogle Scholar
  66. Pond, S.M.; Graham, G.G.; Birkett, D.J. and Wade, D.N.: Effects of tricyclic antidepressants on drug metabolism. Clinical Pharmacology and Therapeutics 18: 191–199 (1975).PubMedGoogle Scholar
  67. Pottage, A.; Nimmo, J. and Prescott, L.F.: The absorption of aspirin and paracetamol in patients with achlorhydria. Journal of Pharmacy and Pharmacology 26: 144–145 (1974).PubMedCrossRefGoogle Scholar
  68. Prescott, L.F.: Gastrointestinal absorption of drugs. Medical Clinics of North America 58: 907–915 (1974a).PubMedGoogle Scholar
  69. Prescott, L.F.: Gastric emptying and drug absorption. British Journal of Clinical Pharmacology 1: 189–190 (1974b).PubMedCrossRefGoogle Scholar
  70. Prescott, L.F.: Clinically important drug interactions; in Avery (Ed) Drug Treatment, p. 193–213 (ADIS Press, Sydney; Publishing Sciences Group, Acton; Churchill Livingstone, Edinburgh 1976).Google Scholar
  71. Raeburn, J.A. and Devine, J.D.: Clindamycin levels in sputum in a patient with purulent chest disease due to cystic fibrosis. Postgraduate Medical Journal 47: 366–367 (1971).PubMedCrossRefGoogle Scholar
  72. Rawlins, M.D.: General mechanisms of drug interactions. Proceedings of a Symposium on Drug Interactions organised by the Biological Council, April 1975. In Press (1976).Google Scholar
  73. Remmer, H.; Schoene, B.; Fleischmann, R.A. and Olderhausen, H.F.: Drug metabolizing enzymes determined in needle biopsy material of human liver. Abstract of Proceedings of the 5th International Congress on Pharmacology p. 191 (Karger, Basel 1972).Google Scholar
  74. Rivera-Calimlim, L.; Dujovne, C.A.; Morgan, J.P.; Lasagna, L. and Bianchine, J.R.: L-dopa treatment failure: explanation and correction. British Medical Journal 4: 93–94 (1970).PubMedCrossRefGoogle Scholar
  75. Rivera-Calimlim, L.; Dujovne, C.A.; Morgan, J.P.; Lasagna, L. and Bianchine, J.R.: Absorption and metabolism of L-dopa by the human stomach. European Journal of Clinical Investigation 1: 313–320 (1971).PubMedCrossRefGoogle Scholar
  76. Rivera-Calimlim, L.; Castaneda, L. and Lasagna, L.: Effects of mode of management on plasma chlorpromazine in psychiatric patients. Clinical Pharmacology and Therapeutics 14: 978 (1973).PubMedGoogle Scholar
  77. Sanchez, N.; Sheiner, L.B.; Halkin, H. and Melmon, K.L.: Pharmacokinetics of digoxin: interpreting bioavailability. British Medical Journal 4: 132–134 (1973).PubMedCrossRefGoogle Scholar
  78. Schanker, L.S.: Drug absorption; in La Du, Mandel and Way (Eds) Fundamentals of Drug Metabolism and Drug Disposition, p.22–43 (Williams and Wilkins, Baltimore 1971).Google Scholar
  79. Schneider, R.E.; Babb, J.; Bishop, H.; Mitchard, M.; Hoare, A.M. and Hawkins, C.F.: Plasma levels of propranolol in treated patients with coeliac disease and patients with Crohn’s disease. British Medical Journal 2: 794–795 (1976).PubMedCrossRefGoogle Scholar
  80. Siurala, M.; Mustala, O. and Jussila, J.: Absorption of acetylsalicyclic acid by a normal and an atrophic gastric mucosa. Scandinavian Journal of Gastroenterology 4: 269–273 (1969).PubMedGoogle Scholar
  81. Sjöqvist, F.; Borga, O. and Orme, M.L’E.: Fundamentals of clinical pharmacology; in Avery (Ed) Drug Treatment, p.1–42 (ADIS Press, Sydney; Publishing Sciences Group, Acton, Churchill Livingstone, Edinburgh 1976).Google Scholar
  82. Sjöqvist, F. and von Bahr, C.: Interindividual differences in drug oxidation: Clinical importance. Drug Metabolism and Disposition 1: 469–482 (1973).PubMedGoogle Scholar
  83. Thorgeirsson, S.S. and Davies, D.S.: Kinetic studies of the N-demethylation of ethylmorphine by a cytochrome P-450-dependent enzyme system in human liver microsomes. Biochemical Journal 112: 30P (1971).Google Scholar
  84. Turmer, A.D.: Personal communication (1974).Google Scholar
  85. Turnberg, L.A.: The absorption of iron after partial gastrectomy. Quarterly Journal of Medicine N.S. 25: 107–119 (1966).Google Scholar
  86. Venho, V.M.K.; Aukee, S.; Jussila, J. and Matilla, M.J.: Effect of gastric surgery on the gastrointestinal drug absorption in man. Scandinavian Journal of Gastroenterology 10: 43–47 (1975).PubMedGoogle Scholar
  87. Volans, G.N.: The effect of metoclopramide on the absorption of effervescent aspirin in migraine. British Journal of Clinical Pharmacology 2: 57–63 (1975).PubMedGoogle Scholar
  88. White, R.J.; Chamberlain, D.A.; Howard, M. and Smith, T.W.: Plasma concentrations of digoxin after oral administration in the fasting and postprandial state. British Medical Journal 1: 380–381 (1974).CrossRefGoogle Scholar

Copyright information

© ADIS Press 1977

Authors and Affiliations

  • R. L. Parsons
    • 1
  1. 1.Department of Clinical PharmacologyGuy’s Hospital Medical SchoolLondonEngland

Personalised recommendations