• Pharmacokinetic principles
• Drug absorption, distribution,
metabolism and elimination
Jan Juřica, PharmD., Ph.D.
Basic Pharmacology
- pharmacodynamics – the study of the efects of the
drugs on receptors, reactions; principles of action
- pharmacokinetics - the study of the movement
of drugs through the body in time.
(absorption, distribution, metabolism, excretion)
= Action of a drug requires presence of
a certain concentration in the fluid
bathing the target tissue.
Pharmacokinetics
Occupation theory: The intensity of
pharmacological response (E) is
proportional to the conentration of
reversible drug-receptro complex
Pharmacokinetics deals with the processes of
absorption,
distribution,
metabolism
excretion of the drug
And their relationship with their biological
(pharmacological) effect
„WHAT DOES ORGANISM DO WITH THE DRUG“
“ADME“
elimination
A
D
M
E
invasion
permeation across the membranes
lipophilic – difusion (passive)
hydrophilic – through the pores
active transport
What does influence the movements of the drug in the body?
physico-chemical properties
lipophilic/hydrophilic properties, molecule
structure, pKa, charge…
AH  A- + H+ B + H+  BH+
Ionized compounds
tend to be less lipid
soluble.
Non-Ionized
compounds tend to be
more lipid soluble.
permeation across the membranes
lipophilic – difusion (passive)
hydrophilic – through the pores
active transport
bonds of the drugs to:
plasma proteins
blood cells in the circulation
tissue
receptors
perfusion of the tissues
a) brain, heart, liver, kidney
b) fat tissue
What does influence the movements of the drug in the body?
physico-chemical properties
lipophilic/hydrophilic properties, molecule
structure, pKa, charge…
AH  A- + H+ B + H+  BH+
OATP, MDR, MRP
diffusion
active transport via
transport proteins
through the
pores
permeation across the membranes
lipophilic – difusion (passive)
hydrophilic – through the pores
active transport
bonds of the drugs to:
plasma proteins
tissue
blood cells in the circulation
receptors
perfusion of the tissues
a) brain, heart, liver, kidney
b) fat tissue
What does influence the movements of the drug in the body?
physico-chemical properties
lipophilic/hydrophilic properties, molecule
structure, pKa, charge…
AH  A- + H+ B + H+  BH+
15
ABC - ATP-BINDING CASSETTE
16
ABC - ATP-BINDING CASSETTE
 MDR - multi drug resistance
 MRP - multidrug resistance asociated protein
 MXR - mitoxantrone resistance protein
 Pgp - P-glykoproteinová pumpa
permeation across the membranes
lipophilic – difusion (passive)
hydrophilic – through the pores
active transport
bonds of the drugs to:
plasma proteins
tissue
blood cells in the circulation
receptors
perfusion of the tissues
a) brain, heart, liver, kidney
b) fat tissue
What does influence the movements of the drug in the body?
physico-chemical properties
lipophilic/hydrophilic properties, molecule
structure, pKa, charge…
AH  A- + H+ B + H+  BH+
Concentration of free drug
Afinity for binding sites
Conc. of protein
A bound drug has no
effect !!!
18
• plasma proteins
• tissue
• blood cells in the circulation
• receptors
19
• most of acidic drugs (at pH of 7.4= anions)
are bound on albumin:
– salicylates, sulfonamides, penicillins
• most of alcalic + neutral drugs (at pH of
7.4= cations) are bound on α1- acidic
gylcoprotein and lipoproteins:
– quinidine, digitoxine, TCA, cyclosporine A
20
• Bonds with plsama proteins are
– reversible
– dynamic
– competitive
21
drug % bound
caffein 10
digoxine 23
gentamycine 50
phenytoin 87
digitoxine 95
diazepam 96
warfarin 98
tolbutamide 99
A bound drug has no effect!
Amount bound depends on:
1) free drug concentration
2) the protein (binding sites) concentration
3) affinity for binding sites
% bound: __[bound drug]__________ x 100
[bound drug] + [free drug]
Bonds in peripheral tissues
• specific for some of the drugs
- tetracycline antibiotics - hydroxyapatit
- chloramfenicol – skin
- grisefulvin - skin
- arsenic – in hair
ABSORPTION
Absorption – permeation of the soluted drug into the body fluids
from the site of administration – necessary for the general
(systhemic) effect
Local effect – on the skin, mucous membranes…
mouth, rectum, vagina
- absorption is fault, can cause difficulties, adverse
effects)
(local aenesthetics, corticosteroids)
Rate and extent of absorption are described by the parameters :
C max - max. concentration of the drug in the plasma after single
administration
T max - time after administration, when is Cmax
F - bioavailability (extent of absorption)
time
Plasmatic concentration of
the drug
Bioavailability
• The fraction of the dose of a drug (F) that
enters the general circulatory system,
F= amt. of drug that reach systemic circul.
Dose administered
F = AUCp.o./AUCi.v.
Extravascular route - 0-100% (resp. 0-1).
Intravenous - 100% = 1
If F is 0-20% = 0-0,2 – not suitable route of administration
(in spite of that fact, some drugs are administered, even if the F ˂ 2-5 %, such
as SET, bisphosphonates).
F = AUCpo/AUCiv
(the same drug, same dose, same patient)
Bioavailability
Bioavailability
• A concept for oral (extravascular) administration
• Useful to compare two different drugs or different
dosage forms of same drug
• depends, in part, on rate of dissolution (which in
turn is dependent on chemical structure, pH, partition
coefficient, surface area of absorbing region, etc.) Also firstpass
metabolism is a determining factor
Influence of the various
bioavailability on the
plasmatic levels of the drug
• Is a measure of bioavailability
Area under curve (AUC)
First pass effect, presysthemic elimination
Factors influencing absorption
Drug-dosage form– tbl./ sol./ supp./ TTS/tbl.subling.
Way of administration
Physico-chemical properties of drugs
- absorptive surface area
- concentration gradient
- ionization, lipofility
- interactions
Other factors influencing the absorption
gender, body weight, plasma volume, gastric
amptying rate,
age - pH, bile, enzyme levels and activity
patophysiological state – liver disseases,
inflammation
simultaneously eaten meal –
acceleration/decelaration
chemical incompatibilities
function of the GIT
Factors affecting pharmacokinetics
Drug dosage forms of the 1st and 2 nd generations
hour
= permeation from the body blood to the tissues and site of the action
is dynamic process
rate - depends on:
bonds (with the plasmatic proteins…)
permeation across the membrabes
blood perfusion through the organ
state - distribution equilibrium; the the proportion of the free
(unbounded) fractions of the drug in the blood and in
the tissues are the same
Barriers – the distribution is limited
blood-brain barrier („leaky areas“ – area postrema),
penicilines X aminoglycosides
placental barrier…
Distribution
Volume of Distribution
Vd = D/C
– Vd is the apparent volume of distribution
– C= Conc of drug in plasma at some time
– D = Total quantity (dose) of drug in system
Vd gives one as estimate of how well the drug is
distributed.
Value < 0.071 L/kg indicate the drug is mainly in the
circulatory system. Values > 0.071 L/kg indicate
the drug has gotten into specific tissues.
Volume of distribution – apparent, hypotethical
the proportion of the quantity of the drug and reached plasmatic
concentration
Volumes of the water in
human body
water in general in
whole the body
extracellularintracellular
intersticial plasma
Perfusion through the organs
organ perfusion rate % heart output
(ml/min/g tkáně)
brain 0.5 14
fat 0.03 4
heart 0.6 4
kidney 4.0 22
liver 0.8 27
musculature 0.025 15
skin 0.024 6
ELIMINATION = biotransformation + excretion
• Kinetics of the first order
= rate of elimination is descending with the
descending concentration in the blood
(linear kinetics)
• Kinetics of the zero order
= rate of elimination is constant (nonlinear
kinetics)
Types of Kinetics Commonly
Seen
• Zero Order Kinetics
• Rate = k
• C = Co - kt
• C vs. t graph is LINEAR
First Order Kinetics
• Rate = k C
• C = Co e-kt
• C vs. t graph is NOT
linear, decaying
exponential.
• Log C vs. time graph is
linear.
First Order Kinetics
Biotransformation – metabolism
Sites of biotransformation
anywhere, where the enzymes are present: plasma, kidney, lungh
GIT, brain, but especially liver
Enzymatic
• biodegradation
• bioactivation (prodrug)
enalapril-enalaprilate
codein-morphine
bromhexin - ambroxol
ELIMINATION
1. Phase : oxidation, hydrolysis
Cytochrome P450, dehydrogenases
2. Phase : conjugation – metabolites are more soluble in the water
Metabolite - effective („more / less / in other way“)
- ineffective
- toxic
CYP 2D6
30%
CYP 1A2
2%
CYP 2C9
10%
other
3%
CYP 3A4
55%
CYP 3A4
CYP 2D6
CYP 2C9
CYP 1A2
other
Genetic polymorfism of CYP 450
INDUCERS of CYP 450
• dexamethason
• phenobarbital
• rifampicine
• phenytoin
• St. John`s Wort (Hypericum perforatum)
• Ginkgo biloba
INHIBITORS of CYP 450
• antidepressants (fluoxetine, fluvoxamine, paroxetine)
• quinine, quinidine
• chloramphenicol, erythromycin
• ketoconazol, itraconazol
• grapefruit juice
5mg tablet + grepfruit
juice
5 mg tablet
Phase I of biotransformation
hydroxylation -CH2CH3  -CH2CH2OH
oxidation -CH2OH  -CHO  -COOH
O-dealkylation -CH2OHCH2  -CH2OH + -CHO
N-dealkylation -N(CH3)2  -NHCH3 + CH3OH
N-oxidation -NH2  -NHOH
oxidative deamination -CH2CHCH3  -CHCOCH3 + NH3
NH2
Other non-microsomal biotransformations
• hydrolysis of esters in plasma (suxamethonium by cholinesterase)
• dehydrogenation of alcoholic and aldehydic group in cytosol in
the liver (ethanol)
• MAO in mitochondria (tyramine, noradrenaline, dopamine,
amines)
• xanthinoxidase (6-merkaptopurine, uric acid)
• enzymes with distinct function (tyrosine-hydroxylase, dopadecarboxylase,
etc.)
Phase II of biotransformation
CONJUGATION
Glucuronides -OH, -SH, -COOH, -CONH wih glucuronyl acid
(UDP- GlcUAc)
Sulphates: with -OH functional group
Acetylates: acetyl CoA with NH2, -CONH2, s aminoacid- group
with gluthathion with -halogen- or -nitrate functional groups, epoxides
sulphates
Excretion
Kidney (urine)
tubular excretion
x tubular reabsorption
liver (bile)
lungh (air)
saliva, skin, hair, breast milk...
Clearance Cl
• Volume of blood in a defined region of the
body that is cleared of a drug in a unit time.
• more useful concept in reality than kel since
it takes into account blood flow rate
• Clearance varies with body weight
• Also varies with degree of protein binding
• MW < 60.000 D (MW albumin = 68.000 D)
• tubular secretion
– organic acids
• furosemid
• thiazide diuretics
• penicilins
• glucuronides
– organic bases
• Morphine
• Atropine
• Histamine…
• tubular reabsorption
Kidney
acidification
acetazolamid (inhibitor of CA)
ammonium chloride
alcalization
sodium bicarbonate
Liver
Billiar excretion, clearance.
enterohepatic circulation
Extraction ratio ER
= proportion of the drug removed durring
the passage through the organ
ER = ca-cv/ca
PHARMACOKINETIC PARAMETERS
PRIMARY
• Bioavailability (F)
• Volume of distribution
(Vd)
• Clearance (Cl)
SECONDARY
• elimination half-life (T1/2)
• elimination constant (Ke)
• AUC (area under the
curve)
• Cumulative index
• Extraction ratio
Repeated administration
• increase in effect – accumulation
senzitization
• decrease in effect
- tolerance - changes at the site of receptor
- chnges in pharmacokinetics
- tachyphylaxis
- resistence – „tolerance“ to the drugs inhibiting cell.
growth or cytotoxic drugs
cytostatics, antiinfectives, antiseptics
• drug dependance
axe po opakovaném podávání efedrinu (pokles vlivu na TK)
rinu
E
E E
0 5 10 15 20 25 30
min
Tachyphylaxis after repeted ephedrine administration
(decrease ineffect on blood pressure)
E = ephedrine administration