Learning Objectives: 4-5 Flashcards
List at least 10 factors determining the rate of absorption after oral administration.
-Release Characteristics of Dosage Form
• Disintegration / deaggregation
• Dissolution of drug from granules
(also dependent on inactive ingredients and formulation variables)
-Physicochemical Properties of Drug
• Complexation • Ionization (acid/base) • Partition coefficient (octanol/water) • Solubility in water
-Physiology of GI Tract
• Colonic retention • Gastric emptying • Intestinal motility • Perfusion of the GI tract • Permeability of gut wall
-GI Tract Abnormalities and Diseases
• Crohn’s disease • Diarrhea • Gastric resection or modification (e.g., in obesity) • Ulcerative colitis
Give approximate values for the transit time of nondisintegrating pellets in the stomach, small intestine, and large intestine.
Fasting -Stomach: quick - 10, 20, 30 min -Small Intestine: 2, 3, 4 hours -Large Intestine: 12, 24, 36 hours With Food -Stomach: delay in delivering drug to SI (where abs. occurs) / changed to hours depending on fat content, high caloric, water (no changes), protein shakes, etc. -SI and LI remain same
Discuss the factors controlling gastric emptying.
-All drugs in solution are absorbed faster from intestine than stomach (irrespective of pH). Any factor affecting the rate of GE will influence the absorption kinetics of a drug given orally in solution.
• Drugs: Some slow gastric emptying and some hasten it with corresponding changes in absorption kinetics of drugs.
• Fasted Stomach: Small / large non-disintegrating pellets = relatively rapid. Large non-disintegrating solids = more erratic and variable.
• Meals: Meals (fats) markedly delay gastric emptying of large non-disintegrating pellets; meals also delay emptying of liquid and small solids. Little effect of meals on small intestine transit time, 2.5 to 4 hours.
Anticipate the role of gastric emptying in the absorption of drugs administered in immediate release, enterically-coated, or modified-release dosage forms.
- Immediate-release: no delay or prolonging of absorption or dissolution
- Enterically-coated: coat with material resistant to acidic environment of stomach but which breaks down in the intestinal fluids // cannot be used when rapid and reliable absorption is required
- Modified-release: (sustained-release dosage forms which stay pretty much intact down the GI tract)
List the physicochemical factors that determine the rate of transport across the gut wall.
Properties of actual drug: size, charge, lipophilicity, polarity
- Drug formulation properties: IM, EC, MR
- Difference between physiochemical factors vs. drug formulations vs. body (Crohn’s disease, intestinal motility, etc.)
Active Transport
- Active transport is the net movement of a substance against a concentration gradient, which can be large (diff. from PFD)
- Maintenance of this gradient requires metabolic energy
- Active transport can therefore be impeded by metabolic inhibitors
- Characteristics in common with passive facilitated diffusion are saturability, specificity, and competitive inhibition
Carrier-Mediated Transport
•Membranes have a specialized function: maintain the internal cellular environment by excluding/removing some materials and sequestering or selectively retaining vital substances
-Many polar compounds with low lipid solubility penetrate membranes much faster than anticipated for passive diffusion through an inert lipoidal barrier
• Specialized carrier-mediated transport systems appear to be responsible: an energy-dependent pathway where specific receptors on the membrane of carriers recognize target molecules and transport them across the cell
• Substrates are often endogenous compounds, or close analogs
• The concept of a carrier stems from the observation of a limited rate of transport at increased substrate concentrations
Concentrating Transporters
Under ACTIVE transport
-These transport systems are called “Concentrating Transporters”
• Influx transporters = those that facilitate transport into cells
• Efflux transporters = those that facilitate movement out of cells
Equilibrating Transporters
Under PASSIVE FACILITATED diffusion
• Relatively few drugs undergo passive facilitated diffusion. Examples are: cytarabine (Hairy Cell Leukemia), gemcitabine (pancreatic cancer)
-In common with other carrier-mediated systems, glucose transport is reasonably specific and is inhibited by other substrates
• These transport systems are called “Equilibrating Transporters.
Paracellular Transport
Go through gaps between cells (Some small polar molecules are not able to traverse the cell membranes)
Passive Diffusion
process by which molecules diffuse from a region of higher concentration to a region of lower concentration
Passive Facilitated Diffusion
• Passive Process
- substance moves down a concentration gradient, using carrier or channel proteins, without net expenditure of energy
- at equilibrium, concentrations in and surrounding the cells remain constant over time
Permeability
Function of the nature of the membranes
• Other major sources of differences among drugs relate to molecular size, lipophilicity, charge and shape
-Cellular membranes: inner lipoidal matrix covered on each surface by either a continuous or a lattice work of protein
• Hydrophobic portions of lipid molecules oriented toward the center, outer hydrophilic regions face surrounding aqueous environment
• Narrow aqueous-filled channels exist between some cells as in capillary membranes and intestinal epithelia
Transcellular Absorption
when the drug moves through cells
Discuss the role of P-glycoprotein and CYP3A in the absorption of substrates for this transport protein.
• CYP3A and P-gp share many substrates and inhibitors
• Suggests that together they form a “barrier” to drug absorption
-Metabolism of CYP3A and efflux transport of PGP are major determinant of rate/extent of absorption
- In this model, drug absorption could be increased either by inhibiting the back transport (P-gp inhibition) or by inhibiting the metabolizing enzymes
- Conversely, inducers of the metabolizing enzymes reduce bioavailability
