Week 3: Pharmacokinetics (ADME)
Membrane permeation by drugs
Direct diffusion through the lipid membrane
This depends on drug conc. gradient and diffusion coefficient. The conc. gradient
depends on the drug’s lipid/water partition coefficient, estimated by the drug’s
distribution between water and a simple organic solvent e.g. heptane.
Ionization:
A drug is more water-soluble in its ionized form but the unionized form is membrane
permeable.
This is required due to the tendency of weak acid- and weak base-drugs to ionize in
aqueous solution, depending on the pH of the environment and the drug’s acid
dissociation constant.
A strong acid has low pKa
A strong base has high pKa
The ionized form is lipophobic, so passive membrane permeation is impeded.
Fractional ionisation determined from Henderson-Hasselbalch equation
ci
for weak acid :log 10 = pH− p K a
cu
ci
for weak base : log10 = p K a −pH
cu
Ci is the concentration of ionized form
Cu is the concentration of unionized form
pKa is the -log(10) of the acid dissociation constant
pH is the -log(10) of the hydrogen ion concentration
When the lipid membrane separates two solutions with different pH, the difference
in ionization on the two sides can lead to an uneven distribution. The ionized
molecules do not readily cross the membrane and there is an effective trapping of
these molecules on the side promoting ionization. E.g. weak base morphine achieves
high concentration in the acidic gastric lumen.
Carrier-mediated transport
For nutrient transport, solute-carrier transporters (SLCs) aid the passive transport of
solutes down their electrochemical gradient and ATP-binding cassette transporters
(ABCs) actively transport solutes. SLCs are further categorised as organic cation
transporters (OCTs) or organic anion transporters (OATs).
Non-lipid-soluble drugs require carriers for membrane transport, but they are not
substrates that are specific for nutrient-specific carriers. But, SLCs are important for
carrier-mediated drug transport in the BBB, GI, renal tubules, biliary tract and
placenta.
, Active transport systems in kidney and liver are important in the elimination of
drugs.
Uphill transport allows high renal clearance
Finite number of transporter molecules leads to saturation and competition
between drugs for transport, exacerbated by the low substrate specificity of
many carriers.
Saturation of carrier-mediated transport is governed by the Michaelis-Menten
kinetics. Upon saturation, the elimination of a drug obeys zero-order kinetics.
Diffusion through aqueous pores
Pinocytosis (of a few large molecules e.g. insulin through BBB)
Absorption
Factors to consider:
How is it absorbed? Orally? Intravenously?
Bioavailability – what percentage of drug is absorbed? E.g. vancomycin has 0% bioavailability
if given orally.
Routes of administration: Gut (enteral) or other routes (parenteral)
Depends on factors: drug chemical properties, target organ and safety.
Enteral/gut/oral absorption:
The intestine is the main absorptive area.
- Weak acids are less ionized in the stomach but will be mostly absorbed in
the more alkaline intestine. Rapid passage of drug from stomach to intestine
is likely to speed up drug absorption.
Lipid-soluble drugs are administered orally and are well-absorbed in the GI tract (by
diffusion)
- These lipid-soluble drugs are delivered directly to the liver where they are
made water soluble by metabolism. This may result in substantial first-pass
elimination. But with metabolism, conjugation and de-conjugation
mechanisms in place, these drugs can have a long half-life.
On the other hand, lipid insoluble or water-soluble drugs are absorbed poorly in the
GI tract.
- They are possible administered parentally.
- They are water-soluble so are directly eliminated by the kidney (renal
excretion).
- Therefore, they have a short half-life.
Factors affecting GI absorption:
- Drug chemical properties or formulation e.g. slow-release drugs to prolong
their action and reduce frequency of administration.
Drugs must dissolve to establish a concentration gradient for
absorption
- GI motility - stasis can slow oral absorption while diarrhoea may allow
insufficient time for complete absorption.
- GI tract disease, first-pass metabolism, entero-hepatic recirculation
- Food and other drugs in bowel lumen e.g. charcoal, cholestyramine. These
adsorb other drugs and limit their absorption.
Food can slow drug absorption by reducing the drug’s
concentration. Also, interactions between the drug compounds and
Membrane permeation by drugs
Direct diffusion through the lipid membrane
This depends on drug conc. gradient and diffusion coefficient. The conc. gradient
depends on the drug’s lipid/water partition coefficient, estimated by the drug’s
distribution between water and a simple organic solvent e.g. heptane.
Ionization:
A drug is more water-soluble in its ionized form but the unionized form is membrane
permeable.
This is required due to the tendency of weak acid- and weak base-drugs to ionize in
aqueous solution, depending on the pH of the environment and the drug’s acid
dissociation constant.
A strong acid has low pKa
A strong base has high pKa
The ionized form is lipophobic, so passive membrane permeation is impeded.
Fractional ionisation determined from Henderson-Hasselbalch equation
ci
for weak acid :log 10 = pH− p K a
cu
ci
for weak base : log10 = p K a −pH
cu
Ci is the concentration of ionized form
Cu is the concentration of unionized form
pKa is the -log(10) of the acid dissociation constant
pH is the -log(10) of the hydrogen ion concentration
When the lipid membrane separates two solutions with different pH, the difference
in ionization on the two sides can lead to an uneven distribution. The ionized
molecules do not readily cross the membrane and there is an effective trapping of
these molecules on the side promoting ionization. E.g. weak base morphine achieves
high concentration in the acidic gastric lumen.
Carrier-mediated transport
For nutrient transport, solute-carrier transporters (SLCs) aid the passive transport of
solutes down their electrochemical gradient and ATP-binding cassette transporters
(ABCs) actively transport solutes. SLCs are further categorised as organic cation
transporters (OCTs) or organic anion transporters (OATs).
Non-lipid-soluble drugs require carriers for membrane transport, but they are not
substrates that are specific for nutrient-specific carriers. But, SLCs are important for
carrier-mediated drug transport in the BBB, GI, renal tubules, biliary tract and
placenta.
, Active transport systems in kidney and liver are important in the elimination of
drugs.
Uphill transport allows high renal clearance
Finite number of transporter molecules leads to saturation and competition
between drugs for transport, exacerbated by the low substrate specificity of
many carriers.
Saturation of carrier-mediated transport is governed by the Michaelis-Menten
kinetics. Upon saturation, the elimination of a drug obeys zero-order kinetics.
Diffusion through aqueous pores
Pinocytosis (of a few large molecules e.g. insulin through BBB)
Absorption
Factors to consider:
How is it absorbed? Orally? Intravenously?
Bioavailability – what percentage of drug is absorbed? E.g. vancomycin has 0% bioavailability
if given orally.
Routes of administration: Gut (enteral) or other routes (parenteral)
Depends on factors: drug chemical properties, target organ and safety.
Enteral/gut/oral absorption:
The intestine is the main absorptive area.
- Weak acids are less ionized in the stomach but will be mostly absorbed in
the more alkaline intestine. Rapid passage of drug from stomach to intestine
is likely to speed up drug absorption.
Lipid-soluble drugs are administered orally and are well-absorbed in the GI tract (by
diffusion)
- These lipid-soluble drugs are delivered directly to the liver where they are
made water soluble by metabolism. This may result in substantial first-pass
elimination. But with metabolism, conjugation and de-conjugation
mechanisms in place, these drugs can have a long half-life.
On the other hand, lipid insoluble or water-soluble drugs are absorbed poorly in the
GI tract.
- They are possible administered parentally.
- They are water-soluble so are directly eliminated by the kidney (renal
excretion).
- Therefore, they have a short half-life.
Factors affecting GI absorption:
- Drug chemical properties or formulation e.g. slow-release drugs to prolong
their action and reduce frequency of administration.
Drugs must dissolve to establish a concentration gradient for
absorption
- GI motility - stasis can slow oral absorption while diarrhoea may allow
insufficient time for complete absorption.
- GI tract disease, first-pass metabolism, entero-hepatic recirculation
- Food and other drugs in bowel lumen e.g. charcoal, cholestyramine. These
adsorb other drugs and limit their absorption.
Food can slow drug absorption by reducing the drug’s
concentration. Also, interactions between the drug compounds and
