Transport of Drugs Across Membranes

Question 1

Membrane Transport Mechanisms

Answer 1

Diffusion
Aqueous channel; aqua porin
Across lipid matrix (=passive diffusion)

Specialised Transport
Carrier Mediated
Vesicular Transport

Question 2

Diffusion Via Aqua Porin

Answer 2

Low molecular size
Hydrophilic
Uncharged

Examples: Urea, ethanol, water

Most drugs don’t use this

Question 3

Diffusion Across Lipid Matrix

Answer 3

-> Passive Diffusion
Important for most drugs in absorption and distribution

Determinants of diffusion
Area across which diffusion happens
Large: Small Intestines, Lungs
Small: Oral, nasal muscosa, rectal admin

Conc. gradient

Lipid solubility of compound; only lipophilic

Determinants of Lipid Solubility
Non Ionisible Compounds (ex steroids)
#OH groups increase: decrease sol. in liquids
#/size of alkyl groups and # halogen atoms
Increase-> increase lipid solubility

    Ionisable Compounds (organic acids and bases)
        Uncharged (R-COOH, R-NH2) -> lipophilic
        COO-; NH3+-> non diffusible as hydrophilic

Degree of Ionisation Depends on:
pH of solution
pKa of compound (pH at which 50% of molecules are
ionised)

Is calculated by Henderson- Hasselbalch equation

Question 4

Carrier Mediated Transport

Characteristics

Answer 4

Capacity (Tm, Km)
Selectivity (ligands)
Comp between substrates
Driving force: conc gradient, 1 ATP cleaved-> 1 molecule 
         transported

Question 5

Carrier Mediated Transport

Active

Answer 5

Driven by ATP

1 active: driven directly by ATP Ex: ABC transporters

2 active: driven by ATP conc gradient Ex: Na dep. transp.

3 active: driven by ATP dep ion and solute gradient
Example: organic anion transporters

Question 6

Carrier Mediated Transport

Facilitated Diffusion

Answer 6

Driving force: conc gradient
Requires transporter
Equilibrative transport; cont. until equilibrium is reached

Equilibrative Nucleoside Transporter (ENT)
Mediates uptake/ efflux of nucleosides from or to blood
Also nucleoside analogues: Antivirals, Anticancer drugs

Glucose Transporters (GLUT1-GLUT12)
Uptake: Glucose: Blood-> Cell
Export: Glucose: Cell-> Blood

GLUT1: RBC
GLUT2: Hepatocytes
GLUT4: Skeletal Muscle
GLUT9: Tubular Cells

Question 7

Carrier Mediated Transport

Primary Active Transport

Answer 7

Exclusively Efflux
Have IC ATP binding domains and ATP activity = ABC transporters (ATP binding cassette)

Example: Multidrug Resistance Transport protein

MDR Family (or Pgp)
transport large basic and neutral molecules
found in: enterocytes, hepatocytes, renal tubular cells,
brain endothelial cells
–> Pgp substrates don’t have CNS effect; contibutes to
BBB
Ex: cetirizine, fexofenadine, vinblastine

MRP Family
MRP2: Hepatocytes
Organic acid type drugs and glucuronides-> bile

MRP1,3: Hepatocytes and Renal Tubular Cells
Organic acid type drugs -> blood and tubular fluid

BCRP (Breast Cancer Resistant Protein)
Transports mainly large basic molecules, some acids

Found: Enterocytes, Hepatocytes, Renal Tubular Cells,
Brain Endothelial Cells

(Same locations and role as Pgp but diff. substrated)

Question 8

Carrier Mediated Transport

Secondary Active Transport

Answer 8

Na Dependent Transport
Import;
Driven by NaK ATPase generated Na gradient
2K in and 3 Na out
Example: Bile Acid Transporter
Na dep. Glucose Transporter
Na dep. Vit C Transporter
Neuronal monoamine transporters NET
Na/I Symporter (thyroid)

Membrane Potential Dependent
Import
Driven by NaK ATPase generated - potential inside
2K in and 3 Na out
–> uptake of cations (low molecular weight)

Example: Organic Cationic Transporters
OCT1: Basolateral Membrane of Hepatocytes
OCT2: Basolateral Membrane of Prox. Tubular Cells
OCT3: Many Tissues

Substrates incl: H2R Antagonists (cimetidine ex)
Procainamide
Pindolol
Metformin
Amiloride

Question 9

Carrier Mediated Transport

Tertiary Active Transport
Na and a KG Dependent Transport

Answer 9

Import
Driven by NaK ATPase generated Na gradient
Driving force for Na/ aKG cotransport

aKG is second conc gradient driving force for antiport

Substrates: anionic and acidic agents

Organic Anion Transporters
OAT1 in basolat. membrane of prox. renal tubular cells
uptake of acidic drugs ex penicillins, loop diuretics
as well as uptake of acidic conjugates of drugs

Question 10

Carrier Mediated Transport

Tertiary Active Transport
Na and GSH Dependent

Answer 10

Import
Driven by NaK ATPase generated Na gradient
Driving force for Na/Cyst cotransport

Cysteine: substrate of GSH-> outward GSH gradient with intake of substrate

Substrates: acids, bases, neutral compounds

Organic Anion Transporting Polypeptides (OATP)
Present in Hepatocytes
Proximal renal tubular cells (digoxin uptake)
Enterocytes: 1st step of intestinal absorption
Ex: Fexofenadine, atenolol, aliskiren

Question 11

Carrier Mediated Transport

Tertiary Active Transport
Na and H Dep Transport: Import

Answer 11

Import
Driven by NaK ATPase generated Na gradient
Drive Na/H antiport

Na/H antiport creates 2nd conc gradient for H/substrate cotransport

Peptide Transporter (enterocytes): Uptake dipeptides
ACE Inhibitors, Beta Lactam ABs
Competition if taken up with milk/ protein rich
substances

Proton Coupled Folate Transporter (Brush border:
Enterocytes)
Uptake of folate and heme

Divalent Metal Transporter (DMT): Enterocytes
Uptake of Fe2+ also toxic Cd2+!!

Question 12

Carrier Mediated Transport

Tertiary Active Transport
Na and H Dependent Transport: Export

Answer 12

Export
Driven by NaK ATPase generated Na gradient

Drives Na/H Antiport-> H import, export of organic cation

MATE: Multidrug and Toxin Extrusion Transporter
Renal tubular cells-> tubular lumen
Liver cells-> bile canaliculi
Placental trophoblast cells-> maternal blood

Substrates for example are
Cimetidine, Ranitidine, Carbachol, Metformin, amiloride, triamterene, cisplatin

MATE inhibitors
Levo- and ciprofloxacin
Mitoxantrone and Irinotecan