Lecture 3: Distribution Flashcards
Drug Transport Process
-paracellular
-transcellular
-carrier mediated
-go from lumen to blood
passive diffusion
-down concentration gradient
-not saturated
-most common
Facilitated Diffusion
-down concentration
-carriers
-saturable
Active transport
-AGAINST concentration
-via TRANSPORTER
-use ATP
-saturable
Passive transport
-diffusion
-faciliatated diffusion (carrier mediated)
Factors determining diffusion
-molecular size
-lipophilicity
-charge
Smaller molecules permeability
high
lipophilic molecules permeability
high
Log P
-higher = more lipophilic
charge molecule permeability
POOR
(True/false) Salicylic acid will exhibit better crossing through the lipid bilayer at higher pH (e.g., in a
basic condition)
-FALSE
-it is charged at higher pH
Rate-limiting factors
-perfusion-rate limiting
-permeability-rate limiting
perfusion rate-limiting factors
-lipophilic compounds
-limited by amount of blood carrying drugs away
-faster distribution
Permeability-rate limiting factors
-hydrophilic compunds
-limited by slow rate of passing the cell membrane
-will not distribute as well
Would brain (0.5 perfusion rate) or muscle (0.025 perfusion rate) show faster distribution of propofol (nonpolar lipophilic compound with perfusion-rate limitation)
brain
major drug binding plasma proteins
-albumin
-a1-acid glycoprotein
-lipoproteins
albumin
-most abundant plasma protein (50%)
-produced in liver
-binds fatty acids, hormones, and weakly acidic drugs
albumin function
-maintain oncotic pressure of blood
albumin serum levels
decreased in liver and kidney disease
a1-acid glycoprotein (AAG)
-aka orosomucoid
-produced in liver
-binds weakly basic drugs (3’ or 4’ amines)
a1-acid serum levels
-increase during acute phase reaction (inflammation and. burns)
-DECREASED in liver and kidney disease
Lipoproteins
-lipophilic protein or complex of protiens and lipids
-HDL, LDL
-binds hydrophobic drugs
-altered in heart disease state
Free drug Hypothesis
-only free drugs:
-exit capillaries
-cross membrane via diffusion
-bind transporters
Plasma protein-binding
is reversible
Free drug concentration
-same on both sides of membrane at equilibrium
Plasma
-liquid component of blood where blood cells are suspended (yellow)
-makes up 55% blood volume
-contains fibrinogen, globulins, albumin
Serum
-blood allowed to coagulate, clot, and settle at bottom of tube
-supernatant fluid
-devoid of blood cells, fibrins, and clotting factors
-contains plasma proteins
Unbound fraction (fu)
Free drug concentration (Cu)/Total drug concentration (C)
Ultrafiltration
-allow only free drug to be filtered
-allow estimate of unbound fraction
Determinants of Vd
-increase when fu increases
-decrease when FuT increases
Ionized compounds show poorer membrane permeability than un-ionized compounds
TRUE
Lipophilic compounds tend to show greater membrane permeability
TRUE
Lipophilic compounds tend to show permeability rate-limited distribution
-FALSE
-PERFUSION rate-limited
Decreased plasma protein binding of high protein-bound drugs will likely increase Vd
TRUE
Vd is expected to be small for a drug that exhibits strong binding to tissue components
FALSE
-it will be large
fut
-unbound drug fraction in tissues
-Vd will be smaller for more unbound franstion
