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Pharmacokinetics -- part 1 --. W.M. Tom Department of Pharmacology University of Hong Kong. Pharmacokinetics . -- refers to the action of the body on the drug, including: absorption distribution elimination -- metabolism & excretion. Drug Disposition. Drug Absorption .

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Pharmacokinetics-- part 1 --

W.M. Tom

Department of Pharmacology

University of Hong Kong


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Pharmacokinetics

-- refers to the action of the body on the drug, including:

absorption

distribution

elimination -- metabolism & excretion


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Drug Disposition


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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.


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Drug absorption

Solids are not absorbed!

Dissolution is usually the rate limiting step!


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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)


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Drug absorptionstomach (pH 1~3)in favour of weak acid absorptionduodenum (pH 5~7)in favour of weak base absorptionileum (pH 7~8)in favour of weak base absorption


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Diffusion Across Membrane

(pH < pKa )

HA

Weak

Acid

(pH > pKa )

A-

(pH > pKa )

B

Weak

Base

(pH < pKa )

BH+


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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


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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


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First-pass effectmouthesophagusstomachsmall intestinecolonrectum


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First - Pass Effect


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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


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Drug Absorption

Parenteral routes

3. subcutaneous injection (SC)

-- under the skin

-- intended for slow absorption

4. others-- inhalation

-- sublingual

-- topical

-- transdermal, etc.


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Absorption, distribution, metabolism and excretion


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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


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LOCUS OF ACTION

“RECEPTORS”

TISSUE

RESERVOIRS

Bound

Free

Free

Bound

ABSORPTION

EXCRETION

Free Drug

SYSTEMIC

CIRCULATION

Bound Drug

BIOTRANSFORMATION


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Saturation of Protein Binding Sites


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Drug displacement from protein binding sites


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Plasma Protein Binding

consequence of drug displacement

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


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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


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The two phases of drug metabolism


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The two phases of drug metabolism


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Proportion of drugs metabolized by the major phase I and phase II enzymes


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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.


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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


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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)


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Part 1 ended


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Pharmacokinetics-- part 2 --

W.M. Tom

Department of Pharmacology

University of Hong Kong


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Time course of action of a single oral dose Time of onset = T1 - T0Time to peak effect = T2 - T0Duration of action = T3 - T1MEC = minimum effective concentration


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Time 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%


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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


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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


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One Compartment IV Bolus Pharmacokinetic Model

Ct = C0 • e – k • t………. (2)

Ct : plasma concentration at time t

C0 : plasma concentration at time 0


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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


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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

orVd = ————— ………………. (4)

C0


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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


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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


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One-compartment pharmacokinetics (single dose, IV)Cp = plasma drug concentrationC0 = plasma concentration at time zerok el = elimination constantelimination half-life t 1/2 = t 2 - t 1


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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


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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


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Bioavailability

Plasma

concentration

(AUC)o

(AUC)iv

i.v. route

oral route

Time (hours)


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Multiple IV Bolus Dose Administration

drug accumulation occurs when repeated doses are given before the drug is completely eliminated

repeated drug administration at dose intervals (t ) will give a steady state with the plasma concentration fluctuating between a maximum (Cmax) and a minimum (Cmin ) value


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Plateau principleCss = steady state concentrationCmax = maximum CssCmin = minimum CssMEC = minimum effective concentrationMTC = minimum toxic concentrationtherapeutic range = MTC - MEC


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Time 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


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Effect of dosage intervals on drug concentration curve 1 -- dosage interval too short; curve 2 -- too long; curve 3 -- ideal


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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


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Time 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


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Combined 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)


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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


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Two-compartment pharmacokinetics (single dose, IV) central compartment (rapid) t 1/2 peripheral compartment (slow) t 1/2


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Part 2 ended


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