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8/12/2019 G 01 Staud Drug Transport
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Literature
Rang & Dale's Pharmacology
Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12th Edition
Study materials at: www.faf.cuni.cz
http://www.faf.cuni.cz/http://www.faf.cuni.cz/8/12/2019 G 01 Staud Drug Transport
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Pharmacology
- studies interactions of drugs with organism
General pharmacology
General relations between drug and body(pharmacokinetic and pharmacodynamic)
Special pharmacologyIndividual drugs/groups of drugs in therapy
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Pharmacology
Pharmacokinetics
Fate of drugs in the organism (absorption, distribution,
metabolism, excretion)
Pharmacodynamics
Effect of a drug on organism interactions with target
molecules (receptor, enzyme, transporter) >pharmacological/toxicological response
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Pharmacology in dru
g development
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Transport of drugsacross biological membranes
Prof. PharmDr. Frantiek taud, Ph.D.
Department of Pharmacology & ToxicologyFaculty of Pharmacy, Charles University
Literature: Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12th EditionZiegler, Mohr, Bieger, Lullmann Color Atlas of PharmacologyRang & Dale Pharmacology
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Drug disposition
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Interactions of drugs with organism
absorption(first- pass)
Tissue
Extravascularadministration
i.v. administration
Plasma
bound fraction
free fraction
elimination
Pharmacokinetics Pharmacodynamics
Therapeutical effect
Biologicalmembrane
distribution
Pharmacological effect
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Biological membrane
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Examples of biological barriers in body
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Physicochemical properties of drugs
Lipid-solubility partition coefficientoil/water.
Degree of ionization ionized (charged)molecules cannot cross biological
membranes.
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Weak electrolytes and influence of pH
AH H+ + A-
acidB + H+ BH+
basis
In acidic pH: AH
BH+In basic pH: A-
B
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Henderson-Hasselbalch equation
AH H+ + A-
acid
B + H+ BH+
base
pHpKformedunprotonat
formprotonateda
log
If pKa of the drug equals pH of the environment, then 50%
of the drug will be ionized.
KaH B
BH
AH
HAKa
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Ionization of aspirin (pKa = 3)
pH
Protonated
(non-ionized) fraction
(%)
Unprotonated
(ionized) fraction (%)
1 99.9 0.10
2 90.0 10.0
3 50.0 50.0
4 9.09 91.9
5 1.00 99.0
6 0.10 99.9
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pH within the body
Plasma 7.4
Stomach 1-3
Duodenum 5-6Ileum, colon 8
Milk 7.0-7.3
Cerebrospinal fluid 7.3
Urine 4-8
Fetus 7.3
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Effect of ionization on drug movement across biological
membranes
Ion trapping
ff f i i i d
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Effect of ionization on drug movement across
biological membranes
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Drug transport across biological membranes
A) Passive diffusion
B) Filtration and bulk flow
C) Active transport
Facilitated diffusion
D) Transport of ion-pairs
E) Endocytosis
F) Efflux transporters
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A) Passive diffusion
The most common transport of drugs
across membranes.
Depends on lipid solubility and ionization.
(only non-ionized fraction can cross)
Governed by Ficks law:
h
CCAP
dt
dm )(** 21
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B) Filtration
Molecules do not penetrate across
membrane but through pores or paracellular
channels (different from diffusion).
Depends on gradient and size of the
molecule.
MW < 100 (urea, lithium, methanol).
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B) Bulk flow
Fast movement through inter-cellular pores.
Transport across endothelia extravasation (except brain).
Driven by hydrostatic and oncotic pressure.
e.g. glomerular filtration through fenestrations incapillaries of the glomerulus.
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C) Facilitated transports
Mediated by a carrier.
These carriers are: specific
saturable (Tmax)
inhibitable (competition)
Includes: active transport andfacilitated
diffusion.
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C) Active transport
Mediated by a carrier.
Energy-dependent (in the form of ATP).
Can run against the concentration gradient.
Is saturable (Tmax) and inhibitable (competition).
Runs in one direction only.
Substrates: mostly endogenous molecules or compounds
with structural similarity (levodopa, a-methyldopa).
Example: active tubular secretion and reabsorption
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C) Facilitated diffusion
Mediated by a carrier.
Is not energy-dependent (in contrast to active transport).
Driven by concentration gradient.Is saturable (Tmax) and inhibitable (competition).
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D) Transport of ion pairs
E.g.: absorption of quarternary ammonium compounds
from GIT.
Formation of neutral complex (with endogenous mucin)
> passive diffusion > dissociation.
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E) Endocytosis
Cellular uptake of
molecules.
Useful in controlled
delivery/gene therapy.
Physiologically:
transport of IgG from
mother to fetus.
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E) Endocytosis
transport of IgG from
mother to fetus
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F) Efflux ABC transporters
Efflux transporter
pumping lipophilic drugs
out of cell.
Important role in:
chemotherapy (resistance)
pharmacokinetics (affectsabsorption, distribution,
elimination).
E.g. P-glycoprotein, BCRP, MRP
Extracellular space
Intracellular space