Lecture 2: Drug Absorption Flashcards
Factors determining movement of drug through membrane
-characteristics of membrane
-mechanisms of passage
-dwell time of drug-mem interface
-physiochemical properties
-pH
-surface area
Small intestine
-site of most absorption
-folds of Kerckring
Folds of Kerckring
-plicae circulares
-surface has villi and microvilli
-increase surface area for absorption
Transit time to small intestine affects
-peak concentration of drug
Mechanisms by which drugs cross biological membranes
-intracellular junctions
-through lipid membranes
-carriers (diffusion/transport)
-endocytosis
Transcellular diffusion
~95% of drug absorption
-dependent on pKa and pH
Increase transcellular diffusion by:
-remove charged groups
-increase lipophilicity
-reduce size
-compromise between solubility and permeability
pKa < pH of basic drug
BH+ < B
pKa > pH of basic drug
BH+ > B
pKa > pH of acidic drug
AH > A-
pKa < pH of acidic drug
AH < A-
Paracellular diffusion
-between tight junctions
-polar molecules
-small channels and small molecules
-very few drugs
Increased permeability of tight junctions by
toxins and insults opening junctionss
selective opening of tight junctions
may be a means to achieve oral absorption of insulin and other proteins
Fick’s Law of Diffusion
dQ/dt (rate of diffusion)= (DAKp/h)(C1-C2)
-D, Kp, and h constant
C1-C2
concentration difference
-usually C1»_space;C2
rate of transport given C1»_space; C2
dQ/dt = PC1
-P is permeability constant
Rate of transport graph
SLIDE 16
-facilitated diffusion (transport) curve
-simple diffusion y=x slope
Taking riboflavin with food
increase absorption
Facilitated diffusion
concentration gradient only
Active transport
may go against gradient
Transport proteins
-can be on apical and basolateral membrane
-move in or out
-efflux if out
P-glycoprotein
-efflux transporter
-limit drug absorption
-enhance elimination
-limit distribution
syncytiotrophoblast
-lots of pgps to prevent drugs from maternal blood going to fetal blood
Endocytosis
-large molecules
-nanoparticle drug delivery
-phagocytosis, macropinocytosis, caveolar and clathrin mediated endocytosis, endocytosis
efflux transporters
move drugs OUT of cell
If a drug is a substrate for pgp in the enterocyte (to gut lumen), how would co-administration with another drug that inhibits pgp change the amount of drug that entered sytemic circulation?
increase
enterocyte pgps
-limit drug absorption to gut lumen
proximal tubule cell pgps
-enhance drug elimination into tubule lumen
Endothelial Cell pgps
-limit drug distribution
-pump out drugs trying yo go to brain or testes
phagocytosis
-solid particle eaten
=phagosome
macropinocytosis
-particle and ECF eaten
=vesicle
caveolar-mediated endocytosis
-caveolar surface proteins recognize what is to be eaten
clathrin-mediated endocytosis
-bind to receptor
-clathrin-coated pit
-clathrin-coated vesicle
non-clathrin and non-caveolar mediated endocytosis
-works the same just dint know which molecule
