Describe the factors affecting drug absorption throughout the gastrointestinal tract.
This question required candidates to draw on knowledge across the syllabus. Many candidates did not appreciate the breadth required to adequately address this question unfortunately providing very detailed information on only aspects of the answer required to pass. Excellent answers described the following: differences between different GI routes/ sites of absorption, mechanisms of absorption including Fick's law of diffusion, drug formulations, drug factors (including concentration gradient, lipid solubility, ionisation, and molecular weight), site factors (including surface area, first pass metabolism, GI wall thickness, blood flow, and GI motility/ transit time). Marks were also given for consideration of drug interactions, enterohepatic recycling, and luminally active drugs.
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Drug factors: |
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A large drug dose will be absorbed more rapidly because of the high concentration gradient |
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Small molecules diffuse more easily |
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Weak acids are better absorbed; lipophilic drugs are better absorbed |
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Stability of the tablet determines the dispersion rate of the drug, and therefore the rate of absorption. This is manipulated intentionally in slow release formulations |
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The smaller the particles, the greater the surface area from which the drug will be eluted |
| Gastrointestinal factors | |
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Gastric emptying is the major determinant of absorption |
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Intestinal motility can increase or decrease absorption (eg. slow gut transit can ensure complete absorption of a drug bezoar) |
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Gut perfusion is a rate-limiting step in drug absorption only for rapidly absorbed drugs, but as perfusion slows it also becomes more important for all other drugs. |
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Surface area of the small intestine is massive (usually, tens of square metres) and this increases absorption. Factors which decrease intestinal surface area (eg. denuded villi due to gastroenteritis, or surgacal short gut) will decrease drug absorption |
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Drugs can be transported by passive diffusion (either paracellular or transcellular); some are actively transported out of the gut lumen, and others may be actively excreted back into it by efflux pumps. |
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Interaction with other drugs and food substances (eg. tetracycline chelating intestinal calcium from milk, thereby forming an insoluble complex which defeats absorption) |
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The emulsifying effect of bile is critical to the absorption of fat-soluble vitamins and steroids |
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Some drugs may be eliminated in the bile only to be reabsorbed in the jejunum |
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Gut bacteria may either deactivate drugs (by metabolisng them) or activate drugs (by metabolism of an inactive precursor). |
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Enterocytes may metabolise drugs before they undergo first-pass metabolism. Injured enterocytes (eg. after ischaemia) may lose their metabolic function. |
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Levine, Ruth R. "Factors affecting gastrointestinal absorption of drugs." Digestive diseases and sciences 15.2 (1970): 171-188.
Prescott, L. F. "Pathological and physiological factors affecting drug absorption, distribution, elimination, and response in man." Concepts in Biochemical Pharmacology. Springer Berlin Heidelberg, 1975. 234-257.
Martinez, Marilyn N., and Gordon L. Amidon. "A mechanistic approach to understanding the factors affecting drug absorption: a review of fundamentals." The Journal of Clinical Pharmacology 42.6 (2002): 620-643.
Chillistone, Shruti, and Jonathan G. Hardman. "Factors affecting drug absorption and distribution." Anaesthesia & Intensive Care Medicine 18.7 (2017): 335-339.