Biopharmaceutics Part A PDF

Biopharmaceutics part A Eytan A. Klausner, PhD Aulton chapter 19, 20 Objectives Be able to describe physiology of the GI tract relevant for drug absorption Be able to describe the transit of pharmaceuticals in the GI tract Be able to describe the barriers to drug absorption Be a...

Biopharmaceutics part A Eytan A. Klausner, PhD Aulton chapter 19, 20 Objectives Be able to describe physiology of the GI tract relevant for drug absorption Be able to describe the transit of pharmaceuticals in the GI tract Be able to describe the barriers to drug absorption Be able to describe the GI membrane and mechanisms of drug transport Oral route of administration By far the most popular Advantages? GI tract - physiology and drug absorption Physiology of the GI tract The GI tract 6 m in length 4 segments Esophagus Stomach Small intestine Large intestine Aulton Mucus Covers the GI epithelium Viscoelastic aqueous gel Large glycoproteins called mucins Role Average thickness 80 mm [5 to 500 mm] Turnover time  The stomach Volume under fasting conditions Aulton Roles of the stomach Absorption? Chyme = uniform creamy consistency pH and secretions of the stomach pH Secretions Acid Gastrin Pepsin Mucus Connection between a tennis court and the small intestine demo.icetheme.com The small intestine Length = 4 – 5 m pH mayoclinic.com  Villi Finger-like projections into the lumen ~ 0.5 – 1.5 mm in length and 0.1 mm in diameter ~ 600 – 1,000 microvilli cover each villus Aulton Roles of the small intestine Absorption from the small intestine Duodenum, jejunum, ileum Ratio of absolute surface area of the human stomach to that of the small intestine is 1 to 3,800 The colon ~1.5 m Aulton Colon = Part of the large intestine that extends from the cecum to the rectum The colon Roles Absorption of sodium ions, chloride ions and water Storage and compaction of feces No villi Is surface area the only factor for absorption? The colon pH Colon is colonized by an extensive number of bacteria Importance for drugs Transit of pharmaceuticals in the GI tract Gastric emptying Gastric emptying time = gastric residence time Highly variable Depends on Nature of dosage form Fed/fasting state Interdigestive myoelectric cycle AKA migrating myoelectric complex (MMC) In fasting state Phase III = housekeeper wave pharmainfo.net  Fed state Peristalsis – contraction of distal stomach Mix and break down food particles and move them towards the pyloric sphincter Pyloric sphincter Empty Retropulsed into the antrum of the stomach Retropulsion = a situation in which something is pushed or forced backwards [wisegeek.com]  Fed state Which dosage form is anticipated to stay in the fed stomach for a longer period of time? A. Pellets B. Capsules C. Liquids D. Disintegrated tablets E. Extended release dosage forms Pellet: a usually small rounded, spherical, or cylindrical body (as of food or medicine) Gastric emptying Physicochemical principles of pharmacy. Florence and Attwood Gastric emptying of drugs In order for a drug to reach the intestine rapidly, how should the dosage form be taken? A. With food B. With water C. Without food and/or water Small intestinal and colonic transit Small intestinal transit has been found to be relatively constant, at around 3 to 4 hours Colonic transit can vary from anything between 2 to 48 hours Barriers to drug absorption Barriers to drug absorption Aulton Aulton Figure 20.7 Environment within the lumen: Gastrointestinal pH The gastrointestinal pH may influence the absorption of drugs in a variety of ways A. Erythromycin is usually administered via enteric coated tablets B. Omeprazole is usually administered via enteric coated tablets C. Both erythromycin and omeprazole are usually administered via enteric coated tablets Environment within the lumen: Luminal enzymes Which type of enzymes might affect drugs or dosage forms? Sulfasalazine A prodrug of 5-aminosalicylic acid Dailymed.nlm.nih.gov Environment within the lumen: Influence of food in the GI tract Complexation of drugs with components in the diet Insoluble or irreversible Tetracycline Food-induced changes in presystemic metabolism Ciclosporin, verapamil Environment within the lumen: Disease state and physiological disorders Local diseases Gastric surgery GI membrane and mechanisms of drug transport Gastrointestinal membrane Main cellular barrier to drug absorption Semi-permeable Aulton Fig 20.8 Mechanisms of drug transport across the membrane Paracellular Transcellular Passive Carrier- Endocytosis diffusion mediated transport Active Facilitated transport diffusion Transcellular pathways Passive diffusion Drug molecules pass across the GI membrane via passive diffusion from a region of high concentration to a region of lower concentration Majority of drugs are absorbed across cells (i.e., transcellularly) via passive diffusion Passive diffusion Aulton Figure 20.10 Passive diffusion Passive diffusion is the preferred route of transport for relatively small A. Hydrophilic molecules B. Lipophilic molecules  Passive diffusion Rate of transport is determined by Physicochemical properties of the drug Nature of the membrane Concentration gradient of the drug across the membrane Passive diffusion dC/dt = k(Cg-Cb) dC/dt - rate of diffusion across a membrane k - proportionality constant Cg - concentration of drug in solution in the GI fluid at the absorption site  Cb - concentration of drug in the blood Passive diffusion k = DA h k - proportionality constant D - diffusion coefficient of drug in GI membrane A – surface area of membrane h – thickness of membrane  Passive diffusion dC/dt = kCg When is this equation relevant?  Passive diffusion Many drugs are weak electrolytes Which form has higher lipid solubility, ionized or unionized? Affects permeability through GI membrane Carrier-mediated transport: Active transport Aulton  Carrier-mediated transport: Active transport Energy dependent Can be transported against a concentration gradient Transport system usually shows a requirement for specific chemical structures  Carrier-mediated transport: Active transport In active transport, the molecules move from regions of A. Low concentration to those of high concentration B. High concentration to those of low concentration Carrier-mediated transport: Active transport Aulton Carrier-mediated transport: Active transport Nutrients Amino acids Sugars Electrolytes Vitamins (B1, B2, B12) Bile salts Active transport Transporters for which of the following compounds would be the most relevant for the absorption of drugs? A. Short peptides B. Sugars C. Electrolytes D. Vitamins (B1, B2, B12) E. Bile salts Carrier-mediated transport: Active transport Can the same drug be absorbed by different mechanisms?  Carrier-mediated transport: Facilitated diffusion No energy input Similarity with active transport Plays a minor role in drug absorption Mechanisms of drug transport Which mechanism(s) require(s) a concentration gradient of the drug as its/their driving force? A. Passive diffusion only B. Carrier mediated transport: Active transport only C. Carrier-mediated transport: Facilitated diffusion only D. A and B E. A and C Mechanisms of drug transport: Active transport The mechanism of active transport usually does not have a requirement for specific chemical structures A. True B. False Endocytosis Plasma membrane of the cell invaginates Invaginations become pinched off Small intracellular membrane-bound vesicles that enclose a volume of material are formed For macromolecules Endocytosis 1. Fluid-phase endocytosis = pinocytosis 2. Receptor-mediated endocytosis 3. Phagocytosis Endocytosis: 1. Pinocytosis Non specific Low efficiency Fat soluble vitamins http://bio1151.nicerweb.com/Locked/media/ch07/pinocytosis.html 2. Receptor-mediated endocytosis http://bio1151.nicerweb.com/Locked/media/ch07/endocytosis-receptor.html  Endocytosis: 3. Phagocytosis For particles > 500 nm Sabin polio vaccine http://bio1151.nicerweb.com/Locked/media/ch07/phagocytosis.html Paracellular pathway Transport of materials in the aqueous pores between the cells rather than across them Florence and Attwood Paracellular pathway Tight junctions join cells together Tightness can vary considerably between different epithelia in the body Absorptive epithelia, such as that of the small intestine, tend to be leakier than other epithelia Paracellular pathway The paracellular pathway decreases in importance down the length of the GI tract Number and size of pores between the epithelial cells decrease Paracellular pathway Ions (e.g., calcium) Sugars Amino acids Peptides For small and hydrophilic charged drugs MW < 200 Efflux of drugs from the intestine Countertransport efflux proteins expel specific drugs back into the lumen P-glycoprotein Expressed in jejunum Requires energy Can work against a concentration gradient Might affect bioavailability of drugs Aulton Review question 1 The transit of materials through the small intestine is A. Relatively constant B. Dependent on the type of material C. Dependent on the fed or fasted state D. Approximately 8 hours E. Dependent on gastric emptying rate Review question 2 The presence of food in the GI tract A. Has no effect on drug absorption B. Increases drug absorption C. Decreases drug absorption D. Only affects drug disposition E. May increase or decrease drug absorption