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what has to occur in order for a drug to exhibit a therapeutic effect?
drug molecules must reach the target in the body
drug molecules must stay there for a proper time and in sufficient concentration
ADME
the processes the drug molecules undergo in the body that represent pharmacokinetics
A: Adsorption
D: Distribution
M: Metabolism
E: Excretion
absorption
drug transport from the administration site to the bloodstream
occurs in GI and pulmonary tracts,
mucous membranes, and cornea
trans-cellular transport
or, occurs on skin surface
paracellular transport!
absorption in the bloodstream
convection and diffusion, binding to formed particles (erythrocytes, leukocytes, platelets), and (lipo)proteins
mostly passive, trans-bilayer diffusion
distribution
drug transport from the bloodstream to tissues
tight capillaries; drug transport into cells
trans-cellular transport
leaky capillaries; drug transport into the extracellular space
paracellular transport
mostly passive, trans-bilayer diffusion
metabolism
enzymatic and spontaneous (e.g., hydrolysis)
the process by which the body chemically alters the structure of a drug, usually in the liver, to facilitate its elimination
bilayer buildup in some cases
typically, no transport is involved
excretion
elimination of a drug into urine, sweat, expired air, feces..
filtration → paracellular transport
secretion and reabsorption → trans-cellular transport
trans-cellular transport
-the movement of drugs through the actual cell membranes, crossing both the apical (outer) and basolateral (inner) sides of the cell.
-this process typically includes passing through various cellular structures, such as the lipid bilayer and cellular organelles.
-lipophilic (fat-soluble) drugs tend to utilize this transport more readily because they can dissolve in the lipid membrane.
-crucial for drugs that need to reach intracellular targets or enter the bloodstream from the site of administration
paracellular transport
-the movement of drugs between adjacent cells, passing through the intercellular space or tight junctions that connect neighboring cells.
-this pathway is particularly relevant for hydrophilic (water-soluble) drugs that may have difficulty crossing lipid-rich cell membranes
tight junctions between cells
elimination
metabolism + excretion
disposition
distribution + elimination (+metabolism)
what must a drug be able to do?
dissolve to an acceptable extent
survive a range of pHs
cross membranes in villi and capillary walls
avoid excessive binding to plasma proteins and lipoproteins
survive liver metabolism
avoid active transport to bile
cross membranes of capillaries and tissue cells
partition into the target organ
avoid partition into undesired places
be selective for its target
avoid binding to significant antitargets (causing toxicity)
what are the minimum requirements for drug bioavailability?
-solubility in water to have a sufficient free concentration
in the stomach and GI juice for GI absorption
in the bloodstream, tissues, and organs to accomplish distribution
-permeability for the membranes mostly by passive trans-bilayer diffusion, for which the drug needs
appropriate lipophilicity and hydrophilicity balance
only drugs with optimal balance pass through several bilayers as required for absorption and distribution
appropriate ionization – ionized molecules do not pass the membrane
biopharmaceutic classification system
-provides assurance of in vivo (in the body) therapeutic equivalence based on extensive in vitro (in the lab) evaluation
-importance of permeability and aqueous solubility of drug substance (including the rate of dissolution of the drug product) for oral bioavailability
-class I drug candidates can obtain FDA bio-waivers reducing human testing
-class II is subdivided for low dissolution rate (IIa) and low product (IIb) solubility
solubility
-the concentration (mol/L) of a drug (solid, liquid, or gas) in a saturated solution, at given temperature and pressure.
-historically, and for practical reasons, it is often given as % w/w or % w/v
saturated solution
when a solid/liquid/gaseous drug is in equilibrium with the solid/liquid/gas phase:
the solvent is not capable of dissolving more drug under the given conditions
the dissolved drug concentration has reached the maximum and does not increase anymore
very soluble
-parts of solvent required to dissolve 1 part of solute = less than 1
-solubility (% w/w) = greater than 50
freely soluble
-parts of solvent required to dissolve 1 part of solute = 1-10
-solubility (% w/w) = 10-50
soluble
-parts of solvent required to dissolve 1 part of solute = 10-30
-solubility (% w/w) = 3-10
sparingly soluble
-parts of solvent required to dissolve 1 part of solute = 30-100
-solubility (% w/w) = 1-3
slightly soluble
-parts of solvent required to dissolve 1 part of solute = 100-1,000
-solubility (% w/w) = 0.1-1
very slightly soluble
-parts of solvent required to dissolve 1 part of solute = 1,000-10,000
-solubility (% w/w) = 0.01-0.1
(practically) insoluble
-parts of solvent required to dissolve 1 part of solute = greater than 10,000
-solubility (% w/w) = less than 0.01
what factors determine solubility?
energy of solution
energy to bring the drug molecule out of the pure drug phase (loss)
for gaseous and liquid drugs – usually small
for solid drugs – can be significant, the higher the energies, the higher the melting points of crystals
energy to create a cavity in the solvent (loss)
significant only in water because of H-bonds
increases with the size of the drug molecule
energy of solute-solvent interactions (gain) → significant in water, low in lipoid phases - solvation
drug-solvent interactions (solute-solvent interactions)
weak, mostly attractive interactions, which may include
electrostatic, H-bonding, dispersion, and
hydrophobic interactions in water
only dispersion interactions in lipoid phases
-solvation is strongest between similar drug and solvent molecules → the “like dissolves like” principle
polymorphs
-the same compound crystallizes in different crystal forms
-they differ in the energy of release from the solute phase
they often have different solubilities
metastable polymorphs
-(less stable forms)
-usually have higher solubility than more stable forms because the release from the solid form requires less energy and cavity and solvation term are independent of the solid form
-they are polymorphs that persist at conditions where the most stable polymorph would not naturally form
amorphous powders
-lack the crystalline structure and thus, have higher solubility than crystalline forms
due to differences in their molecular arrangement and structure
hydrated crystals
solvates of water
tend to exhibit lower aqueous solubility than their anhydrate forms (water-less forms)
solid forms of drugs
often available in several forms
crystalline forms
polymorphs (more than one crystalline form)
amorphous forms (lacks crystalline form)
-if feasible, amorphous form is chosen because of highest solubility
dissolution
is often the rate limiting step in getting the drug into systemic circulation after oral administration
its rate is a critical parameter for solid dosage forms, especially for oral administration
USP dissolution apparatuses that are used to reduce the hydration layer
rotating basket
paddle
reciprocating cylinder
flow-through cell
the dissolution medium may imitate the content of GI tract where the formulation is expected to dissolve
(0.1 M HCl, simulated gastric or intestinal juice), temperature 37C
what are strategies to improve drug solubility?
chemical structure modifications – only in early stages of drug development
modification of physical properties of solid dosage forms
utilization of polymorphism or amorphous state
micronization: break down the crystal lattice of the solid (it is more than just reducing the particle size)
salt formation
formulation of solvent system (solution dosage forms)
adjust pH (use buffer systems): keep drug in ionized state
use appropriate cosolvents (i.e. alcohol, hydrogen bonding organic solvents)
+ surfactants (as excipients)
+ complexation: association between two or more molecules to form a coordination complex
polarized confluent cell monolayer
when the apical (outer) side and basolateral (inner) side have different morphology and membrane protein content
Caco-2 cells
a human colon epithelial cancer cell line, gold standard for intestinal absorption simulations:
differentiated and polarized with intercellular tight junctions
a well-differentiated brush border
typical small-intestinal nutrient transporters
resembling the enterocytes lining the small intestine
Madin-Darby canine kidney (MDCK) cells
susceptible to viral infection, including influenza serotypes
development of new influenza vaccine candidates for humans
identification of P-glycoprotein substrates and inhibitors
cell lines forming confluent monolayer of polarized cells, i.e., having different
apical (AP) and basolateral (BL) sides
absorptive direction of cell monolayer
apical (AP) → basolateral (BL)
cellular uptake of tested compounds
involvement of transporters
the result is the intrinsic
permeability coefficient
comparison with the apparent permeability coefficient (without
inhibition) informs about the efflux or influx
where does drug metabolism occur?
in liver via drug metabolizing enzymes
• two phases: oxidation (I) and conjugation (II)
how do most drugs pass most membranes?
passive trans-bilayer transport
what lipid molecule is most prevalent in mammalian bilayers?
phosphatidylcholine
mammalian bilayers are mainly composed of…
phospholipids
sphingomyelins
glycolipids
cholesterol
main chain-melting temperature (Tm)
the temperature required to change the bilayer from a gel phase to a fluid phase
between 20 and 60 degrees Celsuis
how to increase fluidity in bilayer?
presence of:
unsaturated fatty acids
molecules dissolved in the bilayer
how to decrease fluidity in bilayer?
presence of:
cholesterol
saturated fatty acid chains in phospholipids
rigid hydrophobic molecules that can intercalate between the fatty acid chains
gel phase of bilayer
below Tm (colder)
phospholipid chains extended
tight packing
slow passive transport
liquid/fluid phase of bilayer
above Tm (hotter)
more conformational freedom
more movement
smaller thickness of the bilayer
larger area per phospholipid
more hydration in the headgroup region
faster passive transport
mixed phase (gel and liquid/fluid) of bilayer
at Tm
fastest passive transport!
headgroup agitated water stratum (phosphatidylcholine bilayer)
-12-16 water molecules per headgroup just above the transition temperature (Tm)
-number of water molecules increases with increasing temperature
headgroup stratum/layer
-H-bond acceptors in high concentration
-all hydrating waters are engaged in H-bond
core soft polymer stratum/layer
the first 6-8 methylene segments of the chains
core alkanes status/layer
-the thickness rests on the length of fatty acid chains
-density of hexadecane
what molecules hop between thermal kinks in the bilayer?
small, nonionized molecules (like gases)
water, urea
oxygen, carbon monoxide, carbon dioxide, nitric oxide
nonionized formic acid
what molecules diffuse through larger, water-filled pores?
monovalent ions
protons, sodium, potassium, etc
what molecules diffuse through a heterogenous bilayer?
larger molecules (up to 1000 g/mol)
-most drugs
solubility/diffusion mechanism
solubility/diffusion mechanism
fast drug interaction (“dissolution”) with the headgroups + interface + core depending on drug structure
slower diffusion of the drug to the opposite side of the bilayer
fast drug transport if…
compounds exhibit intermediate strength of interactions in the headgroup strata and in the hydrocarbon core
accumulation of drugs in the bilayer strata is…
a measure of interaction strength between drug and bilayer strata and is characterized by three drug properties:
lipophilicity
amphiphlicity
cephalophilicity
lipophilicity
tendency to accumulate in the hydrophobic core of the bilayer
expressed as the 1-octanol/water partition coefficient P
amphiphilicty
tendency to adsorb to the headgroup/core interface
the polar part interacts with the phospholipid head groups and the lipophilic part is protruding into the bilayer core composed of fatty acyl chains
cephalophilicity
tendency to interact with the phospholipid head groups
role of drug lipophilcity
drug needs to have intermediate strength of interactions with the core (= intermediate logP value) to pass the bilayer
too hydrophilic (polar) drugs (low logP) will not enter the core
too lipophilic (greasy) drugs (high logP) will get stuck in the core
molecules that are too hydrophilic (low logP value)…?
will not enter the core of the bilayer
molecules that are too lipophilic (high logP value)…?
will get stuck in the core of the bilayer
partition coefficient (Nernst’s distribution law)
P = Co/Cw
cO is the concentration in the organic (nonpolar) phase
cW is the concentration in the aqueous phase
the concentrations are measured at equilibrium and refer to the same molecular species
Nernst’s distribution law and solubility
drugs with high P have low solubility in water
can be used to calculate solubility in one phase if the solubility in another phase is known
1-octanol/water partition coefficients history shiii
-discovered by Hansch in 1964
-Albert Leo maintains a database of the partition coefficients
-approach for calculation of the partition coefficient from the drug structure is ClogP
1-octanol/water reference system
resembles membrane/water system with regard to drug partitioning
describes well binding of drugs to proteins
has practical advantages
dissolves most drugs well (water content 2 mol/L)
does not absorb UV VIS light
drug analysis by UV VIS spectrophotometry is straightforward
is easily purified by distillation
shake-flask method (1-octanol/water)
-the phases are pre-equilibrated, and then the drug is added to the phase where it has higher solubility
if a drug solubility in a phase is low, the phase volume can be increased to make the transfer into this phase measurable as the loss from the other phase
the test tube is shaken until equilibrium is achieved (no concentration changes)
the equilibrium drug concentration in both phases is determined in ideal case
-disadvantages
formation of emulsions possible
no verification of the equilibrium
slow-stir method (1-octanol/water)
-the phase volumes are larger than in the shake-flask method
-the phases are gently stirred to remove concentration gradients without disturbing the interface
-drug concentration in each phase is determined
-the time course of the drug partitioning is measured
verifying the equilibrium
P for unstable drugs (hydrolysis, photolysis...) can be determined by fitting
the sieving effect
the peak becomes narrower after each addition of the bilayer
metabolism of drugs
-the liver is responsible for a major portion of drug metabolism, receives blood from:
hepatic artery (25%) carries oxygen
hepatic portal vein (75%) carries nutrients and drugs from the GI tract
-first-pass effect – drug loss in the first contact with liver
-difficult to relate to drug structure
the drug candidates have susceptible functional groups modified
metabolism makes drug molecules…
more hydrophilic
less prone to protein binding
more susceptible to excretion
excretion of drugs
-kidney is the main excretory organ, but GI tract, lungs and skin are also involved
-renal excretion includes
glomerular filtration
active tubular secretion
(carrier-mediated → structure-specific, energy driven)
tubular reabsorption (active or passive)
-filtration is size limited
-passive reabsorption behaves as passive drug transport from filtrate (pH 4.5 – 8.0) to plasma (pH 7.2) – optimum logP value
-active processes are difficult to relate to drug structure
upper limit of drug transport rates (fast drug transport)
~1 second per bilayer
intermediate strength of interactions in the headgroup region, in the hydrocarbon core, and at the interface between them
lower limit of drug transport rates (slow drug transport)
1-2 days
drugs that are supposed to have oral bioavailability and fast general distribution in the body should have…
intermediate amphiphilicity
intermediate lipophilicity
intermediate cephalophilicity
drugs designed for limited distribution close to the site of administration or release from a dosage form should have…
low or high amphiphilicity
low or high lipophilicity
low or high cephalophilicity
if a drug with limited availability is supposed to be given orally…
it needs to be a substrate for active GI transport
number of cell layers served by a capillary in the lungs
1
number of cell layers served by a capillary in the kidneys
2
number of cell layers served by a capillary in the intestines, liver, heart, brain, and spleen
5
number of cell layers served by a capillary in skin, muscles, fat, and bones
15
-a good estimate of the number of membranes the drug molecules need to cross
the number of cell layers ×10
five layers of intestinal wall (apical/inner side)
mucosa – contains villi with capillaries and lacteals inside
submucosa – contains blood and lymph vessels
circular muscle
longitudinal muscle
serosa
internal surface area of intestine is increased by…
plicae (submucosal folds) - several millimeters in depth
villi (~ 1 mm long) with the surface layer formed by enterocytes
microvilli - brush border membrane
(~ 1 micrometer tall); covers the apical side of enterocytes
stomach transit time (gastric emptying) depends on…
temperature
consistency of food
digestibility of food
volume
the stomach prevents the intestine from ‘nonphysiologic’ conditions
low volume of any consistency and composition of food results in…
prolonged stay in the stomach
liquid intake of standard volume (100 - 200 mL) with low nutrient content, hypotonic
-the stomach begins to empty immediately
-the rate at which the stomach empties is described as exponential. this means that the emptying follows a pattern where the remaining volume decreases by a constant proportion over a specific time period.
-the rate of emptying is directly proportional to the volume of the liquid ingested. in other words, larger volumes will empty at a faster rate.
-the time it takes for the stomach to empty (transit time) ranges from 5 to 20 minutes.
-taking a pill with a glass of water not only provides a dissolution medium for the pill but also facilitates quick gastric emptying
liquid intake of standard volume (100 - 200 mL) with high nutrient content, hypertonic, acidic
-result in slower and non-exponential emptying
-the nutrient content contributes to a more gradual and potentially irregular emptying pattern
-the stomach takes more time to process and release the contents into the small intestine.
soft meals
stay in stomach for 30-60 minutes and then the emptying is linear for 1 - 2 hours
chunky and fatty meals
have greatly prolonged transit time – up to 12 hours
solid dosage forms
needs to be disintegrated in stomach, and ideally the particles should be dissolved before entering small intestine
delay in emptying of the stomach will cause…
delayed the drug absorption
degradation of compounds unstable in acidic media (penicillins, cephalosporins)
irritation of gastric mucosa (aspirin)
interdigestive or fasted state
-alternating cycles of
~1 hour quiescence
a state of rest or inactivity in the GI tract
~1 hour activity known as migrating motor complex (regular contractions with high amplitude housekeeper waves (4-5 per min), preceded and followed by irregular contractions)
digestive or fed state
regular contractions:
same frequency of housekeeper waves, however, the amplitude of these contractions is lower compared to the housekeeper waves, suggesting that the contractions are not as forceful
GI motility
-drugs need sufficient residence time in their absorption window for significant absorption.
modified-release dosage forms have to release the drug before or in the absorption window
the residence time can be increased or decreased in diseases with constipation and diarrhea, respectfully
residence time in the small intestine
~4-5 hours
residence time in the large intestine (colon)
~20 hours or more
number of membranes for a drug to pass
a series of membranes (~30 or more)
-microvilli: a part of the cell membrane of enterocytes
-endoplasmic reticulum inside the enterocytes (a series of membranes)
-the cell membrane at the distant (basolateral) end of enterocytes
- mucosal tissue (a series of membranes)
-wall of blood capillaries: for bilayer-crossing compounds (~ two membranes); other compounds cross through the fenestrae
variations along small intestine
pH variation
specific area affected by plicae, villi, and microvilli
lengths and radii of individual segments
the length of small intestine varies between 3 to 7 m, with average 5 m