Pharmacokinetics
-- part 1 --
Pharmacokinetics
-- part 1 --
W.M. Tom Department of Pharmacology
University of Hong Kong
W.M. Tom Department of Pharmacology
University of Hong Kong
Pharmacokinetics Pharmacokinetics
-- refers to the action of the body on the drug, including:
• absorption
• distribution
• elimination -- metabolism & excretion
-- refers to the action of the body on the drug, including:
• absorption
• distribution
• elimination -- metabolism & excretion
Drug Absorption Drug Absorption
Peroral administration (P.O. route)
• swallowing
• commonly known as “oral administration”
• most convenient and economic method of systemic drug delivery
• dosage forms, e.g. tablets, capsules, syrups, etc.
Peroral administration (P.O. route)
• swallowing
• commonly known as “oral administration”
• most convenient and economic method of systemic drug delivery
• dosage forms, e.g. tablets, capsules, syrups, etc.
Drug Absorption Drug Absorption
Peroral administration (P.O. route)
• drug release formulation (e.g. tablets) e.g. particle size, surface area,
excipients (inert substances)
DISINTEGRATION (solid )
DISSOLUTION (solution)
ABSORPTION
SYSTEMIC CIRCULATION (% bioavailability)
Peroral administration (P.O. route)
• drug release formulation (e.g. tablets) e.g. particle size, surface area,
excipients (inert substances)
DISINTEGRATION (solid )
DISSOLUTION (solution)
ABSORPTION
SYSTEMIC CIRCULATION (% bioavailability)
Drug absorption
stomach (pH 1~3)
in favour of weak acid absorption
duodenum (pH 5~7)
in favour of weak base absorption
ileum (pH 7~8)in favour of weak base absorption
Drug absorption
stomach (pH 1~3)
in favour of weak acid absorption
duodenum (pH 5~7)
in favour of weak base absorption
ileum (pH 7~8)in favour of weak base absorption
Diffusion Across Membrane
WeakAcid
WeakBase
B
BH+
(pH > pKa )
(pH > pKa )
(pH < pKa )
(pH < pKa ) HA
A-
Drug Absorption Drug Absorption
• Factors affecting drug absorption by enteral routes
1. Drug dissolution
-- depends on drug formulation of oral preparations
2. pH environment in GI tract
-- unionized form efficiently absorbed
3. Lipid solubility of the drug
-- nonpolar form easily absorbed
• Factors affecting drug absorption by enteral routes
1. Drug dissolution
-- depends on drug formulation of oral preparations
2. pH environment in GI tract
-- unionized form efficiently absorbed
3. Lipid solubility of the drug
-- nonpolar form easily absorbed
Drug Absorption Drug Absorption
• Factors affecting drug absorption by enteral routes
4. Effects of food
-- in general delays drug absorption
5. First pass effect
-- absorption of a drug into the portal circulation
-- drug metabolized by liver before it reaches the systemic circulation
• Factors affecting drug absorption by enteral routes
4. Effects of food
-- in general delays drug absorption
5. First pass effect
-- absorption of a drug into the portal circulation
-- drug metabolized by liver before it reaches the systemic circulation
First-pass effect
mouth
esophagus
stomach
small intestine
colon
rectum
First-pass effect
mouth
esophagus
stomach
small intestine
colon
rectum
Drug Absorption Drug Absorption
• Parenteral routes
1. intravenous injection (IV)
-- directly into a vein
-- 100% bioavailability
2. intramuscular injection (IM) -- into a muscle
-- depends on blood supply
• Parenteral routes
1. intravenous injection (IV)
-- directly into a vein
-- 100% bioavailability
2. intramuscular injection (IM) -- into a muscle
-- depends on blood supply
Drug Absorption Drug Absorption
• Parenteral routes
3. subcutaneous injection (SC)
-- under the skin
-- intended for slow absorption
4. others-- inhalation
-- sublingual
-- topical
-- transdermal, etc.
• Parenteral routes
3. subcutaneous injection (SC)
-- under the skin
-- intended for slow absorption
4. others-- inhalation
-- sublingual
-- topical
-- transdermal, etc.
Absorption, distribution, metabolism and excretion Absorption, distribution, metabolism and excretion
Drug Distribution Drug Distribution
• Drug transfer to various tissues
-- depends on drug lipophilicity and blood flow
• Drug barriers
-- e.g. blood-brain barrier, placenta
• Drug binding to plasma proteins
-- bound drugs are pharmacologically inactive
-- unbound drugs are free to distribute to target tissues
-- different drugs may compete for binding to plasma proteins and displace each other from binding
sites
• Drug transfer to various tissues
-- depends on drug lipophilicity and blood flow
• Drug barriers
-- e.g. blood-brain barrier, placenta
• Drug binding to plasma proteins
-- bound drugs are pharmacologically inactive
-- unbound drugs are free to distribute to target tissues
-- different drugs may compete for binding to plasma proteins and displace each other from binding
sites
Bound Free Free Bound
LOCUS OF ACTION
“RECEPTORS”TISSUE
RESERVOIRS
SYSTEMIC CIRCULATION
Free Drug
Bound Drug
ABSORPTION EXCRETION
BIOTRANSFORMATION
Plasma Protein BindingPlasma Protein Binding
• an increase in free drug concentration of the displaced drug
an increase in drug effect
(be cautious when using a drug of low T.I.)
• a decrease in the duration of action of the displaced drug because more free drugs are available for elimination
• an increase in free drug concentration of the displaced drug
an increase in drug effect
(be cautious when using a drug of low T.I.)
• a decrease in the duration of action of the displaced drug because more free drugs are available for elimination
consequence of drug displacement
Drug Metabolism Drug Metabolism
• modification of the chemical structure by enzyme systems in the body
-- e.g. cytochrome P450 in liver
• these chemical reactions produce water-soluble metabolites which are more readily excreted by the kidneys
-- phase I reaction, e.g. oxidation
-- phase II (conjugation) reaction, e.g. glucuronidation
• drug metabolism activity can be influenced by a variety of drugs
• modification of the chemical structure by enzyme systems in the body
-- e.g. cytochrome P450 in liver
• these chemical reactions produce water-soluble metabolites which are more readily excreted by the kidneys
-- phase I reaction, e.g. oxidation
-- phase II (conjugation) reaction, e.g. glucuronidation
• drug metabolism activity can be influenced by a variety of drugs
Proportion of drugs metabolized by the major phase I and phase II enzymes
Proportion of drugs metabolized by the major phase I and phase II enzymes
Drug Metabolism Drug Metabolism
• enzyme induction
-- results in faster rate of metabolism
-- e.g. in heavy cigarette smokers, alcoholics
• enzyme inhibition
-- results in slower rate of metabolism
-- e.g. taking another drug which uses the same enzyme for metabolism
• biological variations in drug metabolism
-- e.g. genetics, disease states, age, etc.
• enzyme induction
-- results in faster rate of metabolism
-- e.g. in heavy cigarette smokers, alcoholics
• enzyme inhibition
-- results in slower rate of metabolism
-- e.g. taking another drug which uses the same enzyme for metabolism
• biological variations in drug metabolism
-- e.g. genetics, disease states, age, etc.
Drug Excretion Drug Excretion
• in urine
-- by glomerular filtration and renal tubular secretion -- polar water-soluble metabolites readily
excreted while nonpolar forms reabsorbed back to circulation
• in bile and feces
• other routes
-- e.g. in sweat, milk and other body fluids
-- volatile gases by exhalation
• in urine
-- by glomerular filtration and renal tubular secretion -- polar water-soluble metabolites readily
excreted while nonpolar forms reabsorbed back to circulation
• in bile and feces
• other routes
-- e.g. in sweat, milk and other body fluids
-- volatile gases by exhalation
Renal excretion of drugs
-- lipid-soluble and un-ionized drugs are passively reabsorbed through the nephron
-- active secretion of organic acids and bases occurs only in the proximal tubular segment
-- in distal tubular segments, the secretion of H+ favours reabsorption of weak acids (less ionized) and excretion of weak bases (more ionized)
Renal excretion of drugs
-- lipid-soluble and un-ionized drugs are passively reabsorbed through the nephron
-- active secretion of organic acids and bases occurs only in the proximal tubular segment
-- in distal tubular segments, the secretion of H+ favours reabsorption of weak acids (less ionized) and excretion of weak bases (more ionized)
Pharmacokinetics
-- part 2 --
Pharmacokinetics
-- part 2 --
W.M. Tom Department of Pharmacology
University of Hong Kong
W.M. Tom Department of Pharmacology
University of Hong Kong
Dosage EffectsSiteof
Action
PlasmaConcen.
PharmacokineticToxicokinetics
PharmacodynamicsToxicodynamics
Time course of action of a single oral dose
Time of onset = T1 - T0
Time to peak effect = T2 - T0
Duration of action = T3 - T1
MEC = minimum effective concentration
Time course of action of a single oral dose
Time of onset = T1 - T0
Time to peak effect = T2 - T0
Duration of action = T3 - T1
MEC = minimum effective concentration
Time course of drug actionTime course of drug action• time of onset
-- the time taken for the drug to produce a response
• time to peak effect
-- the time taken for the drug to reach its highest blood concentration
• duration of action
-- the time during which the drug produces a response
• elimination half-life ( t 1/2 )
-- the time taken to reduce the drug concentration in the blood by 50%
• time of onset
-- the time taken for the drug to produce a response
• time to peak effect
-- the time taken for the drug to reach its highest blood concentration
• duration of action
-- the time during which the drug produces a response
• elimination half-life ( t 1/2 )
-- the time taken to reduce the drug concentration in the blood by 50%
One Compartment IV Bolus Pharmacokinetic Model
One Compartment IV Bolus Pharmacokinetic Model
Assumptions• drug is mixed instantaneously in blood• drug in the blood is in rapid equilibrium with drug
in the extravascular tissues• drug elimination follows first order kinetics
Assumptions• drug is mixed instantaneously in blood• drug in the blood is in rapid equilibrium with drug
in the extravascular tissues• drug elimination follows first order kinetics
One Compartment IV Bolus Pharmacokinetic Model
One Compartment IV Bolus Pharmacokinetic Model
• rate of concentration change at each time point:
dCp
——— = – k • Cp
dt
…. (1)
Cp : plasma drug concnetration
k : elimination rate constant
• rate of concentration change at each time point:
dCp
——— = – k • Cp
dt
…. (1)
Cp : plasma drug concnetration
k : elimination rate constant
One Compartment IV Bolus Pharmacokinetic Model
One Compartment IV Bolus Pharmacokinetic Model
Ct = C0 • e – k • t
………. (2)
Ct : plasma concentration at time t
C0 : plasma concentration at time 0
Ct = C0 • e – k • t
………. (2)
Ct : plasma concentration at time t
C0 : plasma concentration at time 0
One Compartment IV Bolus Pharmacokinetic Model
One Compartment IV Bolus Pharmacokinetic Model
k • t
log Ct = log C0 – ————— ………. (3)
2.303
Ct : plasma concentration at time t
C0 : plasma concentration at time 0
k • t
log Ct = log C0 – ————— ………. (3)
2.303
Ct : plasma concentration at time t
C0 : plasma concentration at time 0
One Compartment IV Bolus Pharmacokinetic Model
One Compartment IV Bolus Pharmacokinetic Model
Apparent volume of distribution (Vd )
• apparent volume that the drug is distributed into• not a physiological volume
amount of drug in the body X
Vd = ———————————— = ——
drug conc. In plasma Cp
DOSE
or Vd = ————— ………………. (4)
C0
Apparent volume of distribution (Vd )
• apparent volume that the drug is distributed into• not a physiological volume
amount of drug in the body X
Vd = ———————————— = ——
drug conc. In plasma Cp
DOSE
or Vd = ————— ………………. (4)
C0
One Compartment IV Bolus Pharmacokinetic Model
One Compartment IV Bolus Pharmacokinetic Model
DOSE
Vd = ————— ………………. (4)
C0
substitute (4) to (3), I.e. Ct = C0 • e – k • t
DOSE
Ct = ————— • e – k • t ………. (5)
Vd
DOSE
Vd = ————— ………………. (4)
C0
substitute (4) to (3), I.e. Ct = C0 • e – k • t
DOSE
Ct = ————— • e – k • t ………. (5)
Vd
One Compartment IV Bolus Pharmacokinetic Model
One Compartment IV Bolus Pharmacokinetic Model
Half-Life of Elimination ( t 1/2 )
• time taken for the plasma concentration to fall to half its original value
0.693
t 1/2 = ————— ………………. (6)
k
Half-Life of Elimination ( t 1/2 )
• time taken for the plasma concentration to fall to half its original value
0.693
t 1/2 = ————— ………………. (6)
k
One-compartment pharmacokinetics (single dose, IV)
Cp = plasma drug concentration C0 = plasma concentration at time zerok el = elimination constant elimination half-life t 1/2 = t 2 - t 1
One-compartment pharmacokinetics (single dose, IV)
Cp = plasma drug concentration C0 = plasma concentration at time zerok el = elimination constant elimination half-life t 1/2 = t 2 - t 1
One Compartment IV Bolus Pharmacokinetic Model
One Compartment IV Bolus Pharmacokinetic Model
Drug clearance ( CL )
• a measure of he efficiency with which a drug is removed from the body
rate of elimination amount of drug • k
CL = ———————— = —————————
Cp Cp
= Vd • k ………………. (7)
CL total = CL kidney + CL liver + CL others
Drug clearance ( CL )
• a measure of he efficiency with which a drug is removed from the body
rate of elimination amount of drug • k
CL = ———————— = —————————
Cp Cp
= Vd • k ………………. (7)
CL total = CL kidney + CL liver + CL others
One Compartment IV Bolus Pharmacokinetic Model
One Compartment IV Bolus Pharmacokinetic Model
Bioavailability ( F )
• measures the extent of absorption of a given drug, usually expressed as fraction of the administered dose
• intravenous injection, by definition, has a bioavailability of 100%
AUC • CL
F = —————————————— ….. (8)
DOSE
AUC : area under the conc.-time curve
Bioavailability ( F )
• measures the extent of absorption of a given drug, usually expressed as fraction of the administered dose
• intravenous injection, by definition, has a bioavailability of 100%
AUC • CL
F = —————————————— ….. (8)
DOSE
AUC : area under the conc.-time curve
0
20
40
60
80
100
120
140
0 2 4 6 8 10
Plasma concentration
Time (hours)
i.v. route
oral route
Bioavailability
(AUC)o
(AUC)iv
Multiple IV Bolus Dose AdministrationMultiple IV Bolus Dose Administration
• drug accumulation occurs when repeated doses are given before the drug is completely eliminated
• repeated drug administration at dose intervals () will give a steady state with the plasma concentration fluctuating between a maximum (Cmax) and a minimum (Cmin ) value
• drug accumulation occurs when repeated doses are given before the drug is completely eliminated
• repeated drug administration at dose intervals () will give a steady state with the plasma concentration fluctuating between a maximum (Cmax) and a minimum (Cmin ) value
Plateau principle
Css = steady state concentration
Cmax = maximum Css
Cmin = minimum Css
MEC = minimum effective concentration
MTC = minimum toxic concentration
therapeutic range = MTC - MEC
Plateau principle
Css = steady state concentration
Cmax = maximum Css
Cmin = minimum Css
MEC = minimum effective concentration
MTC = minimum toxic concentration
therapeutic range = MTC - MEC
Time course of drug actionTime course of drug action• plateau principle
-- repeated drug administration at fixed dosage intervals will produce a plateau concentration of drug in the blood (I.e. steady state)
• steady state
-- a state at which the rate of drug administration is equal to the rate of elimination
• therapeutic range
-- the range between the minimum effective concentration (MEC) and the minimum toxic concentration (MTC) of a drug
• plateau principle
-- repeated drug administration at fixed dosage intervals will produce a plateau concentration of drug in the blood (I.e. steady state)
• steady state
-- a state at which the rate of drug administration is equal to the rate of elimination
• therapeutic range
-- the range between the minimum effective concentration (MEC) and the minimum toxic concentration (MTC) of a drug
Effect of dosage intervals on drug concentration
curve 1 -- dosage interval too short; curve 2 -- too long; curve 3 -- ideal
Effect of dosage intervals on drug concentration
curve 1 -- dosage interval too short; curve 2 -- too long; curve 3 -- ideal
Blood levels of drugs with intermittent dosage
a typical oral dosage four times a day on a schedule of 10-2-6-10 or 9-1-5-9
Blood levels of drugs with intermittent dosage
a typical oral dosage four times a day on a schedule of 10-2-6-10 or 9-1-5-9
Time course of drug actionTime course of drug action
• loading dose
-- a large dose given to achieve therapeutic concentration rapidly
• maintenance dose
-- a dose given to maintain the drug concentration at steady state
• loading dose
-- a large dose given to achieve therapeutic concentration rapidly
• maintenance dose
-- a dose given to maintain the drug concentration at steady state
Combined Infusion and Bolus AdministrationCombined Infusion and Bolus Administration
• to achieve a therapeutic concentration more quickly is to give a loading dose by rapid IV injection and then start the slower maintenance infusion
Loading dose = Css Vd ........... (9)
Maintenance dose = CL Cp ………. (10)
• to achieve a therapeutic concentration more quickly is to give a loading dose by rapid IV injection and then start the slower maintenance infusion
Loading dose = Css Vd ........... (9)
Maintenance dose = CL Cp ………. (10)
Multi-compartment Pharmacokinetic Model
Multi-compartment Pharmacokinetic Model
• the drug appears to distribute between 2 or more compartments
• the drug is not instantaneously equilibrated in various tissues
• rapidly perfused tissues often belong to the central compartment
• slowly perfused tissues belong to the peripheral compartment
• the drug appears to distribute between 2 or more compartments
• the drug is not instantaneously equilibrated in various tissues
• rapidly perfused tissues often belong to the central compartment
• slowly perfused tissues belong to the peripheral compartment
Two-compartment pharmacokinetics (single dose, IV)
central compartment (rapid) t 1/2
peripheral compartment (slow) t 1/2
Two-compartment pharmacokinetics (single dose, IV)
central compartment (rapid) t 1/2
peripheral compartment (slow) t 1/2