Biopharmaceutics Part A - Specific Aims PDF

[Assignment 3] [Biopharmaceutics part A - Specific Aims] 1\. Be able to describe the advantages of the oral route of administration. Convenient, Cost (cheaper), no trained personnel, Noninvasive, Safer 2\. Be able to describe the mucus of the GI epithelium, including role, main components, and t...

[Assignment 3] [Biopharmaceutics part A - Specific Aims] 1\. Be able to describe the advantages of the oral route of administration. Convenient, Cost (cheaper), no trained personnel, Noninvasive, Safer 2\. Be able to describe the mucus of the GI epithelium, including role, main components, and turnover time. Covers the GI epithelium, Viscoelastic aqueous Gel (have the viscosity of a liquid and a elasticity of a gel) mixed with water, Large glycoproteins called mucins (protect tissues and organs by forming a barrier). Thickness 80 micrometers.\ Role: protection from acids and autodigestion and a mechanical barrier for bacteria.\ Turn over time: rapidly replenished. 3\. Be able to describe the stomach, including its volumes under fed and fasting states, roles, pH, and secretions. Does phase III of the MMC ('housekeeper wave') occur in the fasting stomach or the fed stomach? Vol under fasting less than 50ml, Vol under fed state 1.5 L or 1500ml.\ Roles: Digestion (acid pepsin), Breaks down food and sends to small intestines (Grinding and churning).\ Fasting pH 1-3.5, Fed pH 3-7 (increases in the presence of food)\ Secretions: Acid, Gastrin, Pepsin, Mucus 4\. Be able to describe characteristics of the small intestine and the colon, such as roles, approximate length, pH, and major factors affecting their ability (or limitation) to absorb drugs. Small intestine: pH 7, Length 4-5 m (surface area similar to a tennis court).\ Roles: absorption of nutrients from digested food, extracting vitamins, minerals, carbs, fats and proteins. Digestion.\ Has villi.\ Small intestinal transit constant at 3 -4 hours Colon: Length 1.5 m, pH 6- 7.5, Colonized by extensive \# of bacteria, Important in metabolism some drugs can be metabolized by the bacteria in the colon. Roles: 1. absorption of sodium ions, chloride ions, and water. 2. Storage and compaction of feces. No villi, but has crypts increasing to 10-15 x the surface area. 5\. Be able to explain the patterns of gastric motility in the fasted and fed stomach. What are the 2 major factors that affect the gastric residence time of dosage forms? What are the roles of the pyloric sphincter? 1\. Nature of the dosage form.\ 2. Fed/ fasting state (presence of food)\ \*gastric emptying= gastric residence time (highly variable). Peristalsis- contraction of distal stomach (mix and break down food particles and move them to the pyloric sphincter)\ Pyloric sphincter (empty, retropulsed into the antrum of the stomach). 6\. Be able to describe gastric residence times of drugs: What is the connection between the size of the dosage form or the meal, and gastric residence time? Why would the drug probably reach the intestine faster if it is administered with water, in comparison to administration with food or on an empty stomach? 7\. Be able to describe typical transit times of drugs in the small and large intestines. 8\. Be able to describe barriers to drug absorption in the gut lumen and unstirred water layer. How can gastrointestinal pH, food (including grapefruit juice), or disease states affect drug absorption? Which types of luminal enzymes are most likely to affect drugs and dosage forms and how? Which type of excipients can lipases digest? Drug needs to remain in solution, not become bound to food or other material within the GI tract, and not precipitate. It also needs to be chemically stable so as to withstand the pH of the GI tract and must be resistant to enzymatic degradation in the lumen. The drug then needs ot diffuse across the mucous layer without binding to it, across the unstirred water layer and subsequently across the GI membrane the main cellular barrier. ANY OF THESE BARRIERS CAN PREVENT SOME OR ALL OF THE DRUG REACHING SYSTEMIC CIRCULATION AND CAN THEREFORE HAVE DETRIMENTAL EFFECT ON ITS BIOAVAILABILITY. 9\. Be able to describe major characteristics of the GI membrane and mechanisms of drug transport across it. Which mechanism is the most common for drug absorption? Separates the lumen of the stomach and intestines from the systemic circulation. Main cellular barrier to the absorption of drugs from the GI tract.\ Two main mechanisms of transport across the membrane Transcellular (across the cells- passive diffusion, carrier mediated transport, endocytosis) and paracellular ( between the cells). Transcellular: passive diffusion is the most common for drug absorption. 10\. Be able to describe passive diffusion of drugs, including which drugs are most likely to pass through that route \[Answer: small lipophilic molecules\], and factors that affect the rate of transport. In the diffusion process across the GI membrane, when are 'sink conditions' maintained? Is the concentration of the drug in the blood substantial in comparison to the concentration of the drug in the GI fluids at the absorption sites? Answer: Passive diffusion is when drug molecules pass across the GI membrane from a region of high concentration (lumen) to a region of lower concentration (blood). Most drugs are absorbed across cells (transcellularly) via passive diffusion. Small lipophilic molecules are most likely to pass through using this route. The rate of transport is determined by physicochemical properties of the drug, nature of the membrane, and concentration gradient of the drug across the membrane. 'Sink conditions' are maintained when the concentration gradient is at least 10x greater than the concentration of the substance on the inside of the cell membrane. When the concentration of the drug in the blood is substantially lower 'sink conditions' are met. It means that the concentration of the drug in the blood does not affect the diffusion rate. Only the concentration of the drug in the gut lumen affects the diffusion rate. 11\. Be able to describe active transport of drugs across the GI membrane: Is it mediated by carriers? Does it require investment of energy by the cells, and how does this affect the ability to transport drugs against a concentration gradient? Is it a saturable mechanism? Which molecules (including drugs) can use this mechanism for transport? Can drugs use more than one mechanism of transport for absorption? Transporters for which compounds would be the most relevant for drug absorption, short peptides, sugars, electrolytes, vitamins (B1, B2, B12), or bile salts? Does this mechanism require that the transported molecules will have specific chemical structures? Answer: Yes, active transport of drugs it is mediated by carriers. The energy required is ATP due to moving materials through the cell membrane. This helps with transporting drugs against a concentration gradient because it cannot be done without energy. Active transport is a saturable mechanism because when all the transporters are occupied, increasing the concentration of drug will not increase the rate of the active transport. Molecules that use this mechanism are nutrients, some vitamins, and bile salts. Drugs may use more than one mechanism for drug absorption. Transporters for short peptides are the most relevant for drug absorption. Active transport does require that the transported molecules have specific chemical structures. 12\. Be able to describe drug transport by facilitated diffusion. Is this mechanism important for the absorption of many drugs? Answer: Drug transport by facilitated diffusion requires no energy input. The similarity to active transport is that both mechanisms use transporters (unlike, for example, passive diffusion) and because the number of transporters is limited both mechanisms can be saturated. Facilitated diffusion plays a minor role in drug absorption. Carrier-mediated transport through facilitated diffusion requires a concentration gradient of the drug as its driving force (passive diffusion does too). 13\. Be able to describe the major characteristics of endocytosis, including its 3 major types. Answer: Endocytosis characteristics: - 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 3 major types: - Pinocytosis - Receptor-mediated endocytosis - Phagocytosis 14\. Be able to describe the drug transport mechanism that might enable some drug macromolecules (including oral Sabin polio vaccine) to be absorbed. Answer: Endocytosis (and more specifically phagocytosis) is the drug transport mechanism enabling some drug macromolecules to be absorbed, which applies to particles larger than 500 nm. 15\. be able to describe the paracellular pathway for drug transport. Which types of drugs are anticipated to use this mechanism for transport? Answer: Paracellular pathway is typically used for drugs that are poorly lipid soluble and have a small MW like atenolol. Drugs that are poorly lipid soluble but have a higher MW like gentamycin are not able to utilize this pathway because in order for the pathway to occur, a drug must be small enough to go between the cells. This movement occurs specifically between adjacent cells in the tight junctions of the intestine. 16\. Be able to describe efflux of drugs in the intestine. What is the main protein in the small intestine that is responsible for this phenomenon? Can efflux affect the bioavailability of some drugs? If yes, what would be the effect? Answer: Drug efflux in the intestine refers to the active transport drugs **out of enterocytes back into the intestinal lumen**, reducing their absorption. The **main protein responsible** for this is **P-glycoprotein (P-gP),** an ATP-binding cassette (ABC) transporter found in the small intestine. **Efflux can significantly affect drug bioavailability** by limiting oral absorption, especially for substrates like **digoxin, paciltaxel, and cyclosporine.** Increased P-gP inhibition (verapamil or quinidine) can **enhance drug absorption**, potentially leading to toxicity. 17\. Review questions. - 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 - 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 [Biopharmaceutics part B -- Specific Aims] 18\. Be able to describe factors in the Noyes-Whitney equation that affect the dissolution rate of drugs in the GI tract, including food, surfactants in gastric juice and bile, degree of agitation, and volume of fluid in the stomach. Is the diffusion coefficient of the drug in the GI fluids likely to be increased or decreased in the presence of food? Is an increase in gastric and/or intestinal motility more likely to increase or decrease the dissolution rate of a sparingly soluble drug, and how is this connected to the thickness of the diffusion layer? Will a large volume of fluid increase or decrease the dissolution rate? Answer: dC/dt=DA(Cs-C)/h dC/dt=rate of dissolution of drug particles D=diffusion coefficient \[of drug in GI fluids\] A= effective surface area \[of drug in contract with GI fluids\] Cs= saturation solubility in the diffusion layer C=concentration \[of drug in GI fluids\] H= thickness of the diffusion layer Factors affecting dissolution rate: Environment of the GI tract can affect parameters of equation and dissolution rate: 1. Food, 2. Surfactants in gastric juice and bile, 3. Degree of agitation, and 4. Volume of fluid. The diffusion coefficient of the drug in the GI fluids may be decreased by the presence of food. \*food will increase the viscosity of the GI fluids. Solid foods need to dissolve prior to absorption. Surfactants in gastric juice and bile may affect the solubility of the drug in the GI fluids via micellization. The thickness of the diffusion layer will be influenced by the degree of agitation experienced by each drug particle in the GI tract. An increase in gastric and/or intestinal motility may increase the dissolution rate of a sparingly soluble drug. The volume of fluid available for dissolution depends on the position of the drug in the GI tract and the timing with respect to meal intake. In the stomach the volume of fluid will be influenced by the intake of fluid in the diet. A large volume of fluid increases the dissolution rate. 19\. Be able to explain the connection between particle size, surface area, and dissolution rate. Is reduction of particle size anticipated to increase the absorption of all drugs? If not, what would be the rate limiting step in the absorption process, so that reduction of particle size can increase the absorption? Answer: Smaller particle size increases surface area, enhancing the dissolution rate. Usually, the reduction of particle size will not lead to enhanced drug absorption. However, when the drug dissolution is the rate-limiting step for absorption (also termed dissolution rate limited absorption), then the size reduction will lead to enhanced drug absorption. 20\. Be able to explain whether the use of micronized drug is confined to oral preparations and if not then to which other preparations can micronization be advantageous. Answer: Reduction of particle size is not confined to oral preparations. Reduction of particle size can be beneficial or important in ophthalmic suspensions, topical ointments and creams, and pulmonary delivery systems. 21\. Be able to explain for drugs that are weak electrolytes, whether the solubility of weak acids or weak bases will be higher in the stomach or small intestine. If a drug that is a weak base is administered 2 hours after the administration of a drug that blocks acid secretion (e.g., cimetidine), will the bioavailability of the drug be increased or decreased? Answer: The solubility of weak acids is higher in the small intestine. If a weak basic drug such as ketoconazole is administered 2 hours after the administration of cimetidine, the bioavailability of ketoconazole will be reduced. 22\. Be able to explain the mechanism in which salt forms of drugs can increase dissolution rate. Does the administration of a weak acid (e.g., naproxen) lead to the formation of a fine precipitate in the stomach? How does the fact that the precipitate formed after administration of a salt of a weak acid is fine, affects dissolution rate? Will weak acids that precipitated in the stomach dissolve mostly in the stomach or in the intestine? Which drug is more appropriate to treat toothache, naproxen or naproxen sodium? Answer: Salt forms affect the pH of the diffusion layer, and therefore the saturation solubility of the drug in the diffusion layer. The administration of a weak acid such as naproxen leads to the formation of coarse (i.e., not fine) precipitation. After the administration of naproxen sodium, a salt, the precipitation is fine. When the fine precipitation reaches the small intestine, because of the larger surface area the redissolution is faster. Weak acids will be dissolved mostly in the small intestine. The drug that is more appropriate for the treatment of toothache is naproxen sodium. 23 Be able to explain the rationale of administration of strongly acidic salt forms of weakly basic drugs (e.g., chlorpromazine hydrochloride). How will this affect the pH and the solubility of the drug in the diffusion layer surrounding the drug particles and the dissolution rate of the drug in the stomach? Answer: The rationale of administering strongly acidic salt forms of weakly basic drugs is to create more rapid dissolution. This is because the pH of the diffusion layer is lower than the environment in the stomach. The weak basic drug will dissolve faster in the diffusion layer that is more acidic (because of the hydrochloride salt). Weakly basic drugs can dissolve in the acidic environment of the stomach. However, salts of weak bases can dissolve even faster due to the effect of the salt (hydrochloride) on the pH of the diffusion layer. 24\. Be able to describe factors beyond bioavailability in the selection of salts, and to provide (two) examples of salts that are commonly used as forms of drugs. Be able to describe if there is a use for salt forms that are poorly soluble, and what other approach (without changing the pH of the stomach) can be used to alter the pH in the diffusion layer. Answer: Factors beyond bioavailability in the selection of salts are chemical stability, hygroscopicity, manufacturability, and crystallinity. Two examples of salts that are commonly used are sodium salts of acidic drugs, and hydrochloride salts of basic drugs. There is a use for poorly soluble salt forms which is extended-release dosage forms such as suspensions. To alter the pH in diffusion layer without changing the stomach pH it is possible to add basic/acidic excipients. 25\. Be able to describe the factors affecting the concentration of drug in solution in the GI fluids. Answer: 1. Complexation - increases or decreases absorption which can be beneficial or detrimental to drug absorption. 2. Adsorption- Concurrent administration of pharmaceuticals and remedies containing solid adsorbents (e.g., antidiarrheal mixes) may cause the adsorbents to interfere with drug absorption from the gastrointestinal tract. 3. Chemical stability -- if the drug is unstable in GI fluids, the drug available for absorption will be reduced. 4. Micellar solubilization -- may increase solubility. The ability of bile salts to solubilize drugs is dependent on the lipophilicity of the drug. 26\. Be able to describe whether complexation of the drug can increase or decrease absorption. With what drugs can complex while they are in solution in the GI tract? Can drugs form complexes with excipients in the dosage form? Is the complexation of drugs with cyclodextrins reversible? Can complexation with cyclodextrins increase bioavailability, or does it typically decrease bioavailability? Answer: Complexation of a drug can result in either an increase or decrease in its absorption. Tetracycline that interacts with milk is an example of a decrease in absorption. Cyclodextrins can increase the absorption of drugs such as ketoconazole by forming more water-soluble complexes to increase bioavailability. Streptomycin and mucin are examples of complex forming in solutions in the GI tract as well. Drugs can form complexes with excipients in the dosage form such as phenobarbital and polyethylene glycol 4000. The complexation of drugs with cyclodextrins is reversible. Cyclodextrins most commonly increase the bioavailability of water-insoluble (i.e., poorly soluble) drugs. 27\. Be able to describe interaction of drugs with adsorbents in the GI tract. What might be a possible therapeutic use of the adsorbent activated charcoal? Answer: Concurrent use of drugs containing adsorbents in the GI tract can interfere with the absorption of drugs in the GI tract as they will reduce the rate and extent of absorption. 28\. Be able to describe a very common cause of drug instability in the GI tract. To increase stability in the stomach, should the dissolution rate of the drug be increased or decreased? What are 2 possible approaches to delay drug dissolution until the drug reaches the intestine? Answer: A very common cause of drug instability in the GI tract is chemical instability. Instability in GI fluids is usually caused by acidic or enzymatic hydrolysis. To increase stability in the stomach, the dissolution rate should be decreased, because then there will be more drug particles and less drug molecules in the solution. For erythromycin, there are two possible approaches to delay drug dissolution until the drug reaches the intestine. One is enteric coating of free base erythromycin, and the other is using an erythromycin salt, erythromycin stearate. 29\. be able to explain whether bile salts may solubilize drugs in the GI tract.