Biopharmaceutics 3-4

  • Created by: LBCW0502
  • Created on: 10-04-18 21:24
What is drug absorption?
The process of taking up various body fluids, drugs etc. through the mucus membranes (epithelial cell membrane covered with mucus) or skin to reach the bloodstream
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Which three components increase SA of intestinal epithelium for absorption?
Folds, villi and microvilli
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What are the pre-requisites for drug absorption?
Drug in solution, in contact with absorbing membrane (SI) for sufficient length of time, drug must have appropriate physicochemical properties to be absorbed. Drug has to cross basement membrane and diffuse across lamina propria into blood/lymph
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What are the challenges with oral drug absorption?
Changeable gastric/intestinal motility, variable GE, short contact time with narrow absorption window, fluctuating pH levels along GI tract, high enzymatic activity in GIT, intestinal mucosa in formidable barrier to absorption
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Describe features of oral drug absorption
Drug flow is very fast and provides skin conditions for most drugs. Apical membrane considered to be main barrier for absorption. Basement membrane more fluids and allow passage of drug
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What are the two ways in which drugs can be absorbed?
Passive diffusion and specialised mechanism (active absorption) - a drug can be absorbed by more than one mechanism (one mechanism usually predominates)
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In what form does the drug need to be in to passive diffuse across a cell membrane?
Unionised form
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What are the pathways of drug absorption?
Passive diffusion (transcellular), carrier mediated transport, paracellular, transcytosis
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What are the intestinal drug absorption barriers?
Reach site of absorption (SI) intact, bulk contents, water layer, mucus layer, apical cell membrane, cell interior (aqueous)
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Describe features of intestinal mucosa barriers
Unstirred water layer. Static layer of water (molecule must diffuse across layer). Thickness important. Unstirred water layer can be rate-limiting in the absorption process (small lipophilic molecules with a large permeability constant)
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Describe features of the intestinal mucus layer
Hydrated gel layer covering epithelial cells, mucus secreted by goblet cells, thickness, suspension of mucoproteins (bind drug/decrease absorption rate), barrier to macromolecules (protein-based drugs)
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PK slides
PK slides
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Are acids unionised at a low pH?
Yes
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Are bases unionised at a high pH?
Yes
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What does the pH partition hypothesis predict?
Acidic drugs are absorbed from the stomach and basic drugs are absorbed from the intestine
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How do you calculate the log D (pH) for acids?
Log P - Log [1 + 10^ (pH-pKa)]
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How do you calculate the log D (pH) for bases?
Log P - Log [1 + 10^ (pka-pH)]
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What does a low log P value indicate?
Slow rate of absorption (remains in aqueous phase)
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What does a high log P value indicate?
Slow rate of absorption (in membrane, doesn't want to partition back into aqueous phase despite readily partitioning in oily phase)
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What does a intermediate log P value indicate?
Absorption rate is maximal - optimum balance between molecule entering membrane and leaving
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pH-partition hypothesis
Graphs - descriptions and explanations
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Describe the modification of the pH partition hypothesis to account for the paracellular pathway
Small molecules can cross intestinal epithelium via paracellular route due to effect of 'solvent' drag. Low mwt water soluble drugs cross membranes due to transmusocal water flux (J, ms or sm) - change in equation
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Describe features of the sieving coefficient
Determined by nature of pores and size/physicochemical characteristics of molecule. Sieving coefficient describes the ability of a molecule to pass through the aqueous channels. Value of 1 (molecules moves through pores at same rate as water)
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Water soluble molecules with what mwt cannot cross the membrane via the paracellular route?
Mwt > 270 D
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Do anionic molecules have a higher or low sieving coefficient than cationic/neutral molecules?
Lower
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What are the implications of the sieving coefficient for low log P compounds?
Negligible transcellular absorption. Transport through paracellular route is important. Change in sieving coefficient due to increase in size of compound has huge effect on absorption (e.g. mwt > 270 g/mol cannot pass)
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What are the implications of the sieving coefficient for high log P compounds?
Transcellular absorption predominates. Paracellular route negligible
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Why are there other exceptions/limitations to the pH-partition hypothesis?
Due to variations in: pH, SA, GE, dissolution, ion pairing, presence of bile, first pass metabolism, efflux from cells etc.
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Describe features of SA of stomach
Small SA in stomach (little absorption). Large SA in SI (more absorption)
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Describe features of GE rate
GE and not intestinal permeation is often rate limiting (many factors influence emptying rate)
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Describe features of dissolution rate of dosage form
Drugs in solution prior absorption, dissolution/rate limiting. pH requirements for dissolution are opposite to that required for membrane transfer e.g. acidic drug in stomach, decrease pH/ionisation, increase permeation but decrease dissolution
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What is the rule of thumb for a medium dose drug?
If intrinsic solubility < 1% over pH range 1-7 at 37 degrees Celsius, there are issues with absorption. If intrinsic solubility < 0.1% over pH 1-7 and 37 degrees Celsius, there are serious issues with absorption
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Describe features of manufacturing variables for formulation
Important to understand processes the drug must undergo prior to absorption. Type of dosage form influenced steps between administration of dosage form and its absorption. Greater number of steps before drug in solution leads to lower bioavailability
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What are the formulation factors?
F decreases in this order: aqueous solution, aqueous suspension, soft gelatin capsule, hard gelatin capsule, uncoated tablets and coated tablets
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Describe features of ion pair
Charged drugs may interact with oppositely charged endogenous ions. Producing absorbable complexes with high lipid solubility. Reason why quaternary ammonium compounds (ionised at all pH) are absorbed by interacting with negatively charged bile salts
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Describe features of bile salts and fat absorption pathways
Specialised mechanisms exist for fat absorption in the GIT. Bile salts secreted in to jejunum are efficient emulsifiers of fat in the diet. Act as reservoir for lipophilic drugs (absorption)
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Describe features of GIT and first pass metabolism
Major role in determining how much drug reaches systemic circulation. Drugs exhibit high hepatic extraction ratio e.g. beta blockers, analgesics, tricyclic antidepressants (extensively metabolised in liver). Less active drug in systemic circulation
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Describe features of efflux mechanism (p-glycoprotein)
Uptake of medicine in cell, Pg pump spanning membrane and pumping out medicine. Inhibitor molecules (MDRI) block Pg pump to allow medicine to accumulate inside cell
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What are the two main reasons why the pH-partition hypothesis fails?
Large SA of SI and absorption doesn't follow predicted trend at low and high log P (D) values - other limitations/exceptions also have significant effects and the hypothesis can be modified to account for the paracellular route
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