Absorption, Distribution,

Metabolism, Excretion
( Pharmacokinetics)

Setyo Purwono
Bagian Farmakologi & Terapi
Fakulta Kedokteran, Universitas Gadjah Mada
 Plasma Site of
Dosage Effects
Concen. Action

Pharmacokinetics Pharmacodynamics
Why Study Pharmacokinetics (PK) and
Pharmacodynamics (PD)?

Individualize patient drug therapy

Monitor medications with a narrow therapeutic index
Decrease the risk of adverse effects while maximizing
pharmacologic response of medications
Evaluate PK/PD as a diagnostic tool for underlying
disease states
Clinical Pharmacokinetics
The science of the rate of movement of
drugs within biological systems, as
affected by the absorption, distribution,
metabolism, and elimination of
medications
 Pharmacokinetics
LOCUS OF ACTION TISSUE
RECEPTORS RESERVOIRS
Bound Free Free Bound

ABSORPTION Free Drug EXCRETION

SYSTEMIC
Bound Drug CIRCULATION

BIOTRANSFORMATION
 Absorption
Must be able to get medications into the patients body
Drug characteristics that affect absorption:
Molecular weight, ionization, solubility, &
formulation
Factors affecting drug absorption related to patients:
Route of administration, gastric pH, contents of GI
tract
Absorption in the Pediatric Patient
Gastrointestinal pH changes
Gastric emptying
Gastric enzymes
Bile acids & biliary function
Gastrointestinal flora
Formula/food interaction
Time to Peak Concentration
100
90
80
concentration

70
60 IV
50 Oral
40 Rectal
30
20
10
0
0 5 10 20 30 60 120 180
minutes
 Distribution
Membrane permeability
cross membranes to site of action
Plasma protein binding
bound drugs do not cross membranes
malnutrition = albumin = free drug
Lipophilicity of drug
lipophilic drugs accumulate in adipose tissue
Volume of distribution
 PRINCIPLE

Drugs appear to distribute in the body as if it were

a single compartment. The magnitude of the drugs
distribution is given by the apparent volume of
distribution (Vd).

Vd = Amount of drug in body Concentration in Plasma

Pediatric Distribution
Body Composition
total body water & extracellular fluid
adipose tissue & skeletal muscle
Protein Binding
albumin, bilirubin, 1-acid glycoprotein
Tissue Binding
compositional changes
Metabolism
Drugs and toxins are seen as foreign to
patients bodies
Drugs can undergo metabolism in the lungs,
blood, and liver
Body works to convert drugs to less or
more active forms and increase water
solubility to enhance elimination
Metabolism
Liver - primary route of drug metabolism
Liver may be used to convert pro-drugs
(inactive) to an active state
Types of reactions
Phase I (Cytochrome P450 system)
Phase II
 Phase I reactions (Oxidation)
Cytochrome P450 system
Located within the endoplasmic reticulum
of hepatocytes
Through electron transport chain, a drug
bound to the CYP450 system undergoes
oxidation or reduction
Enzyme induction
Drug interactions
Phase I reactions types
Hydrolysis
Oxidation
Reduction
Demethylation
Methylation
Alcohol dehydrogenase metabolism
Phase II reactions (conjugation)
Polar group is conjugated to the drug
Results in increased polarity of the drug
Types of reactions
Glycine conjugation
Glucuronide conjugation
Sulfate conjugation
 Elimination
of drugs from the body

M KIDNEY LIVER
A
J filtration metabolism
O secretion secretion
R (reabsorption)

M LUNGS OTHERS
I
N exhalation mother's milk
O sweat, saliva etc.
R
Elimination
Pulmonary = expired in the air
Bile = excreted in feces
enterohepatic circulation
Renal
glomerular filtration
tubular reabsorption
tubular secretion
 Elimination by the Kidney
Excretion - major
1) glomerular filtration
glomerular structure, size constraints,
protein binding

2) tubular reabsorption/secretion
- acidification/alkalinization,
- active transport, competitive/saturable,
organic acids/bases
- protein binding

Metabolism - minor
Elimination by the Liver
Metabolism - major
1) Phase I and II reactions

2) Function: change a lipid soluble to more

water soluble molecule to excrete in kidney

3) Possibility of active metabolites with same or

different properties as parent molecule

Biliary Secretion active transport, 4 categories

Pediatric Elimination
Glomerular filtration matures in relation to
age, adult values reached by 3 yrs of age
Neonate = decreased renal blood flow,
glomerular filtration, & tubular function
yields prolonged elimination of medications
Aminoglycosides, cephalosporins,
penicillins = longer dosing interval
The enterohepatic shunt
Drug Liver

Bile Bile formation

duct
Biotransformation;
Hydrolysis by glucuronide produced
beta glucuronidase
gall bladder

Portal circulation

Gut
 Plasma Concentration 10000

First Order Elimination

1000

100

10

1
0 1 2 3 4 5 6
Time
logCt = logC0 - Kel . t
2.303
Plasma Concentration Profile after a
Single I.V. Injection

10000
Distribution and Elimination
Plasma Concentration

Elimination only
1000
C0
100

10

Distribution equilibrium
1
0 1 2 3 4 5 6

Time
 lnCt = lnC0 Kel.t

t1/2 = 0.693/Kel

When Ct = C0, then Kel.t = 0.693. This is the

time for the plasma concentration to reach half the
original, i.e., the half-life of elimination.
PRINCIPLE

Elimination of drugs from the

body usually follows first order
kinetics with a characteristic
half-life (t1/2) and fractional rate
constant (Kel).
First Order Elimination
Clearance: volume of plasma cleared of drug per unit
time.
Clearance = Rate of elimination plasma conc.
Half-life of elimination: time for plasma conc. to
decrease by half.
Useful in estimating: -
time to reach steady state concentration. -
time for plasma concentration to fall after dosing is
stopped.
 Multiple dosing
On continuous steady administration of a drug, plasma
concentration will rise fast at first then more slowly and reach a
plateau, where:
rate of administration = rate of
elimination ie. steady state is reached.
 Single dose
Loading dose
7

6
Therapeutic
Plasma Concentration

5 level

3
Repeated doses
2
Maintenance dose
1

0
0 5 10 15 20 25 30

Time
The time to reach steady
state is ~4 t1/2s

Concentration due to
repeated doses

Concentration due to a single dose

 Pharmacokinetic parameters
Get equation of regression line; from it get Kel, C0 , and AUC

Volume of distribution Vd = DOSE / C0

Plasma clearance Cl = Kel .Vd

plasma half-life t1/2 = 0.693 / Kel

Bioavailability (AUC)x / (AUC)iv

 (AUC)o
Bioavailability =
(AUC)iv
70

60
50 i.v. route
Plasma concentration

40
30 oral route

20
10

0
0 2 4 6 8 10
Time (hours)
 Bioavailability

Definition: the fraction of the administered

dose reaching the systemic circulation
for i.v.: 100%
for non i.v.: ranges from 0 to 100%

e.g. lidocaine bioavailability 35% due to

destruction in gastric acid and liver metabolism

First Pass Effect

 Bioavailability
Destroyed Not Destroyed Destroyed
in gut absorbed by gut wall by liver

to
Dose systemic
circulation
PRINCIPLE

For drugs taken by routes other than the i.v.

route, the extent of absorption and the
bioavailability must be understood in order
to determine what dose will induce the
desired therapeutic effect. It will also
explain why the same dose may cause a
therapeutic effect by one route but a toxic or
no effect by another.