Pharmacokinetics -- part 1 -- W.M. Tom Department of Pharmacology University of Hong Kong W.M. Tom Department of Pharmacology University of Hong Kong.

Pharmacokinetics

-- part 1 --

Pharmacokinetics

-- part 1 --

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 Disposition

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.


• 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

Solids are not absorbed!

Dissolution is usually the rate limiting step!



• drug release formulation (e.g. tablets) e.g. particle size, surface area,

excipients (inert substances)

DISINTEGRATION (solid )

DISSOLUTION (solution)

ABSORPTION

SYSTEMIC CIRCULATION (% bioavailability)


• 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-


• 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


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



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


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

First - Pass Effect First - Pass Effect


• Parenteral routes

1. intravenous injection (IV)

-- directly into a vein

-- 100% bioavailability

2. intramuscular injection (IM) -- into a muscle

-- depends on blood supply


1. intravenous injection (IV)

-- directly into a vein

-- 100% bioavailability

2. intramuscular injection (IM) -- into a muscle

-- depends on blood supply



3. subcutaneous injection (SC)

-- under the skin

-- intended for slow absorption

4. others-- inhalation

-- sublingual

-- topical

-- transdermal, etc.


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

Saturation of Protein Binding Sites

Drug displacement from protein binding sites

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

The two phases of drug metabolismThe two phases of drug metabolism

The two phases of drug metabolismThe two phases of drug metabolism

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)

Part 1 endedPart 1 ended

Pharmacokinetics

-- part 2 --

Pharmacokinetics

-- part 2 --





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


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


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



• 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



Ct = C0 • e – k • t

………. (2)

Ct : plasma concentration at time t

C0 : plasma concentration at time 0

Ct = C0 • e – k • t

………. (2)





k • t

log Ct = log C0 – ————— ………. (3)

2.303



k • t

log Ct = log C0 – ————— ………. (3)

2.303





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



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



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



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



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


MTC = minimum toxic concentration

therapeutic range = MTC - MEC

Plateau principle

Css = steady state concentration

Cmax = maximum Css

Cmin = minimum Css


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

Part 2 endedPart 2 ended

Pharmacokinetics -- part 1 -- W.M. Tom Department of Pharmacology University of Hong Kong W.M. Tom Department of Pharmacology University of Hong Kong.

Documents

drug absorption factors

drug absorption solids

drug dissolution

drug disposition slide

drug absorption stomach

general delays drug

route drug release formulation

bioavailability slide