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/


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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


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


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

G 01 Staud Drug Transport

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