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Utrecht university campus ‘de Uithof’Dept. of Pharmaceutical Sciences
Division of Pharmacology
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Bachelor and master education
PhD training
Research expertise
Ferdi Engels, PhD‐ Associate professor of pharmacology‐ Director of Undergraduate School
of Science
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for today
1. Understand the main concepts of pharmacokinetics
Main concept
2. Be able to apply this new knowledge
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Pharmacologyis about drugs……….
Drugs = chemicals that alter physiological processes in the bodyfor treatment, prevention, or cure of diseases
input output
‐ dose‐ frequency of administration‐ route of administration
‐ no effect‐ beneficial effects‐ adverse / toxic effects
(administration of the drug) (biological response)
7onset, intensity, and duration of therapeutic effects
Pharmacologyis about drugs……….
Drugs = chemicals that alter physiological processes in the bodyfor treatment, prevention, or cure of diseases
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What does the body do to the drug?
What does the drug do to the body?
pharmacokinetics
pharmacodynamics
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9Rosenbaum ‐ Basic pharmacokinetics and pharmacodynamics: an integrated textbook and computer simulations, 1st ed. (2011)
Course Topic 1 Course Topic 2
Thursday, June 15Lecture on topic 1Workshop on topic 1
Friday, June 16Lecture on topic 2Workshop on topic 2
10Rosenbaum ‐ Basic pharmacokinetics and pharmacodynamics: an integrated textbook and computer simulations, 1st ed. (2011)
Examples of common daily doses and dosing intervals
input output
‐ dose‐ frequency of administration‐ route of administration
‐ no effect‐ beneficial effects‐ adverse / toxic effects
(administration of the drug) (biological response)
onset, intensity, and duration of therapeutic effects
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Pharmacokinetics
derives from Greek words:pharmackon = drugkinetikos = moving
Study of drug movement into, around, and out of the bodyor
ADME = absorption, distribution, metabolism, and elimination
Time course of drug concentrations in body compartmentsLippincott’s illustrated reviews: Pharmacology 5th ed (2012)
12Rosenbaum ‐ Basic pharmacokinetics and pharmacodynamics: an integrated textbook and computer simulations, 1st ed. (2011)
Assumption: plasma concentration reflects drug concentration at site of action
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Why study pharmacokinetics?
‐ Natural variation in population yields average ADME characteristics‐ ADME characteristics may be influenced by age, sex, disease, drug use, etc.‐ Therapeutic range of drugs may vary
Guys With Large Dongles Totally Make Perfect Internet Connections
GentamycinantibioticWarfarinanticoagulantLithiumbipolar disorderDigoxinatrial fibrillationTheophyllineCOPD, asthma
Methotrexateoncolytic, DMARDPhenytoinantiseizureInsulinantidiabeticCiclosporinimmunosuppressant
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Why study pharmacokinetics?
‐ Natural variation in population yields average ADME characteristics‐ ADME characteristics may be influenced by age, sex, disease, drug use, etc.‐ Therapeutic range of drugs may vary
Rosenbaum ‐ Basic pharmacokinetics and pharmacodynamics: an integrated textbook and computer simulations, 1st ed. (2011)
MEC = minimum effective concentrationMTC = maximum tolerated concentration
Therapeutic range – between MEC and MTC
unsafeunsafe
uneffectiveuneffective
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Routes of drug administration
Meyer & Quenzer – Psychopharmacology: Drugs, the Brain and Behavior (2005)
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Oral vs. intravenous administration
absorption phase
elimination phase
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ADME ‐ Drug absorption
Drug absorption requires movement across membranes(except after intravenous application)
Goldberg & Gomez‐Orellana ‐ Nature Reviews Drug Discovery 2, 289‐295 (April 2003)
a = transcellular pathwayb = paracellular pathwayc = transcytosis and receptor‐
mediated endocytosisd = absorption into the
lymphatic circulation viaM‐cells of Peyer's patches
most usual
antigen‐presentingcells
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ADME ‐ Drug absorption
Rate of transmembrane diffusion determined by:‐ concentration gradient‐ permeability of barrier (membrane)
Lipid diffusion
Lipophilic and uncharged drug molecules are absorbed fastest !!
logP pKa
therefore
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ADME ‐ Drug absorption
tan[ ]
[ ]oc ol
water
drug
drug
2 1log 2 10
100P P
2 100log 2 10
1P P lipophilic
hydrophilic
Partition coefficient P
Lipophilic drugs are absorbed faster
Log P instead of P (smaller range of values)separatory funnel
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ADME ‐ Drug absorption
Acid dissociation constant pKa• quantitative measure of the strength of an acid in solution
[ ]log
[ ]
ApH pKa
HA
• at pH = pKa, half of the acid is protonated
[ ] [ ] [ ]aK
HA A H
Henderson‐Hasselbalch equation
Uncharged drugs are absorbed faster
The effect of pH on drug ionisation
Waller et al ‐Medical Pharmacology and Therapeutics (2005)
Drug ionisation is dependenton pH and pKa
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ADME ‐ Drug absorption
Aspirin (a.k.a. acetylsalicylic acid) – pKa = 3.5
Stomach: pH ≈ 2Intestines: pH ≈ 6‐7
example
example
Q: Where is aspirin absorbed best?
Q: Explain alkaline diuresis used withaspirin poisoning.
by IV sodium bicarbonate
A: Uncharged in stomach, charged in intestines
BUT
What about its dissolution in acid environment?What about surface area for uptake?
[ ] [ ] [ ]aK
HA A H Le Chatelier’s principleWhen a change is imposed on a systemat equilibrium, the equilibrium will shiftto counteract the change.
buzzing moment
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ADME ‐ Drug absorption
kabs = Absorption rate constant
http://www.boomer.org/c/p4/c03/c0318.html
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ADME ‐ Drug absorption
http://tmedweb.tulane.edu/pharmwiki/doku.php/bioavailability_the_first_pass_effect
Incomplete drug absorption through: Incomplete release from the dosage form Degradation in the GI lumen Poor permeation across GI epithelial barrier Active efflux into GI lumen Biliary excretion Metabolism
First‐pass effect:1 g vs. 2 g dose
Barr – Drug Inform. Bull. 3: 27‐45 (1969)
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ADME ‐ Drug absorption
F = BioavailabilityExtent to which a drug reachesthe systemic circulation
Example: Diclofenac Fiv = ?100% Ftabl = 50%
( )*100tablet
iv
AUCF AUC
http://tmedweb.tulane.edu/pharmwiki/doku.php/bioavailability_the_first_pass_effect
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ADME ‐ Drug distribution
Blood• about 5.5 liter (8% of body weight)• composed of blood cells and plasma
Plasma• about 55% of blood volume• about 90% water• further contains proteins, glucose, minerals, amino acids,hormones, CO2, waste
Serum• plasma without fibrinogen and other clotting factors
albumin
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Drugs may bind to plasma proteins
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[ ] [ ] [ ]k
kD P DP
free drug bound drug+ = plasma concentration Cp
clinically important easy (and cheap) to measure
ADME ‐ Drug distribution
according to the law of mass action:
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ADME ‐ Drug distribution
Raffa et al – Netter’s illustrated pharmacology (2005)
Central compartment Peripheral compartment
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ADME ‐ Drug distribution
70 kg maleplasma 3.5 Lextracellular fluid 14 Lbody water 42 L
https://www.easycalculation.com/medical/plasma‐volume‐calculator.php
500 mg paracetamol143 mg/L36 mg/L12 mg/L
Plasma concentration after:
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ADME ‐ Drug distribution
Vd = Volume of distributionDistribution of drug between plasmaand tissues
0
( )
( / )d
total amount of thedrug inthebody mg DV
drug blood plasma concentration mg L C
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ADME ‐ Drug distribution
from: Brown & Tomlin, Pharmacokinetic principles. In: Tomlin, Pharmacology & Pharmacokinetics (2010)
Extracellular fluid volume0.2 L/kg
Total body water0.6 L/kg
Plasma volume0.05 L/kg
logP = 4.63
42,658 fold preferencefor octanol
www.drugbank.ca
115 L/kg =8000 L for a 70 kg male
Apparent volumeof distribution
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ADME ‐ Drug metabolism
Brown & Tomlin, Pharmacokinetic principles. In: Tomlin, Pharmacology & Pharmacokinetics (2010)
• Mainly in the liver• To make drugs morehydrophilic (for betterelimination by kidney)
• To inactivate drugs
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ADME ‐ Drug metabolism
Brown & Tomlin, Pharmacokinetic principles. In: Tomlin, Pharmacology & Pharmacokinetics (2010)
“DNA passport for everyone”
“Asians, start low doseEast Africans, increase dose quickly”
fast vs. poormetabolizers
ADME ‐ Drug metabolism
http://genomemag.com/whats‐your‐metabolizer‐rate
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ADME ‐ Drug elimination
Drug excretion can occur through:• exhalation• bile ‐‐> faeces• sweat, saliva• kidney
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http://tmedweb.tulane.edu/pharmwiki/doku.php/pharmacokinetics
Cl = Clearance
Volume of plasma completelycleared of drug in a unit of time
ADME ‐ Drug elimination
kel = Elimination rate constant
Fraction of drug eliminated per unit time (hour‐1)
el dCl k V
Looking at it from 2 angles….
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ADME – The whole stuff
Q: how to calculate plasma drug concentrationat any given time?
0elk t
tC C e 0ln lnt elC C k t
i.e. first order elimination kinetics& 1‐compartment model
intravenousadministration
distribution is fast cf. with absorption and elimination
y = b + ax
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ADME – The whole stuff
Drug rapidly equilibrateswith tissue compartment
Drug equilibrates with tissuecompartment much slower
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ADME – The whole stuff
t½ = Elimination half‐lifeTime taken for a drug concentrationto be reduced by a half
0elk t
tC C e
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0 00.5elk t
C C e
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0.693el
t k
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ADME – The whole stuff
oraladministration
intravenousadministration
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ADME – Multiple dose drug administration
Adams et al – Pharmacology for nurses. A pathophysiological approach, 2nd ed (2008)
Loading dose
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Summary – 5 pharmacokinetic parameters
Distribution Metabolism
Elimination
Absorption
kabs F Vd Cl t½
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• Adams, Holland, Bostwick – Pharmacology for nurses.A pathophysiological approach, 3rd ed (2010)
Further reading
• Goodman And Gilman‘s The pharmacological basisof therapeutics, 12th ed (2010)
• Hitner, Nagel – Pharmacology. An introduction.6th ed (2011)
(there are so many good pharmacology books……)
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Further reading
• Rang and Dale’s Pharmacology. 7th ed (2011)
• www.rxkinetics.com/pktutorial/1_1.html
• http://pharmacologycorner.com/
• http://handwrittentutorials.com/
• Pea – Pharmacokinetics in everyday clinicalpractice. 1st ed (2012)
• Lecture handouts: www.staff.science.uu.nl/~engel110/Faro2017