Membrane Transporters and Drug Response

2. Membrane Transporters and Drug
Response

3. Introduction
• Cell membrane – Barrier
• Selectively permeable
• Drug absorption, distribution, elimination
• Specialized transport proteins

4. Transport Mechanisms

5. • Diffusion

6. • Protein-mediated Transport:

7. • Endocytosis/Exocytosis

9. Membrane Transport Proteins
• Channels
• Carriers

10. Channel Proteins
• Passive transport
• Protein-lined passageways
• Speed of transport
• Signalling in Nervous system

11. • Drugs – Receptors
• Nicotinic AcetylCholine Receptor

12. Selectivity of ion channels
• Size of central pore
• Cations and anions
• nAChr
• K+ Leak channels

14. Gating of Ion Channels
• Regulation of opening of pore
• Gating:
Voltage
Ligand
Mechanical

18. Carrier Proteins
• Actually binds to a specific molecule and
physically carries it across the membrane via a
conformational change
• Energy may or may not be required
• Slower than channels
• Drugs – resemble endogenous ligands

19. Passive Carriers
• Facilitate the downhill transport of substances
across membranes
• No energy input
• Glucose Transporters

20. Active Carriers
• Transport of solutes against their gradients
• Requires energy
• 3 types:
ATP-driven Ion Pumps
Coupled transporters
ABC transporters

21. ATP-Driven Ion Pumps
• Utilize the energy liberated by ATP hydrolysis
to move ions across membranes, against their
gradients.
• Na+-K+-ATPase Pump:
2 K+ in, 3 Na+ out

23. Coupled Transporters
• Use the energy stored in ion gradients to
actively transport molecules across membranes
• Secondary Active Transporters
• 2 mechanisms:
Symport
Antiport

24. Symport
• The carrier protein transports two solutes in
the same direction

25. Antiport
• One ion traverses the membrane in one
direction and another metabolite is
transported in the other direction.

26. ABC Transporters
• ATP-Binding Cassette superfamily

27. Efflux Pumps

28. Family Member Alias Expression Function
ABCA
ABCA1
To
ABCA12
Ubiquitous
Removal of cholesterol and PLs onto HDL
particles
Drug resistance
Surfactant protection
ABCB
ABCB1
to
ABCB11
MDR1,PGP
Ubiquitous
Multidrug resistance
Phosphatidylcholine transport
Iron transport
Bile salt transport
ABCC
ABCC1
to
ABCC12
MRP
Ubiquitous
Drug resistance
Organic anion transport
Nucleoside transport
Chloride ion transport
Sulfonylurea receptor
ABCD
ABCD1
to
ABCD4
ALD1,ALDR
PMP70
Peroxisomes VLCFA transport regulation
ABCE ABCE1 OABP Ovary, testes, spleen Oligoadenylate-binding protein
ABCF
ABCF1
ABCF2
ABCF3
ABC50 Ubiquitous
ABCG
ABCG1
ABCG2
ABCG4
ABCG5
ABCG8
Human white
ABCP, MXR, BCRP
Ubiquitous
Cholesterol transport
Drug resistance
Sterol transport

29. GENE NAME NO OF FAMILY
MEMBERS
DISEASES
ABCA 12 Tangier Disease, Stargardt Syndrome
ABCB 11 Bare Lymphocyte Syndrome Type I, X Linked
Sideroblastic Anemia with Ataxia
ABCC 13 Dubin-Johnson Syndrome, Pseudo-Xanthoma,
Cystic Fibrosis
ABCD 4 Adrenoleukodystrophy
ABCE 1
ABCF 3
ABCG 5 Sitosterolemia

30. P-Glycoprotein
• Permeability glycoprotein/ MDR1
• Intestinal epithelium, hepatocytes, renal
proximal tubular cells, adrenal gland and
capillary endothelial cells (BBB)
• Pumps out hydrophobic substances

32. • Overexpressed in human cancer cells
• Multi-drug Resistance
• Transports a variety of substances with
different chemical structures
• Clinical trials: Drugs that inhibit P-gp used in
the treatment of highly drug-resistant cancers

33. MRP
• Multidrug Resistance associated Protein/
Canalicular Multispecific Organic Anion
Transporter 1 (cMOAT)
• Actions similar to P-gp
• Functions in biliary transport

34. BCRP
• Breast Cancer Resistance Protein
• Mitoxantrone and Camptothecin analogues
• Expressed in placenta
• Enhances excretion of xenobiotics
• Secretion of vitamins in human milk

35. SLC Transporters
• 48 families
• Passive transport, Facilitated diffusion and
Ion-channel transport
• Transport of substrates In and Out of the cell
• OATP, OCT, SGLT, MATE

36. OATP
• Organic Anions across cell membrane
• Endogenous substrates:
Bile acids, Bilirubin, thyroid and steroid
hormones
• Drugs:
Anti-cancer, Antibiotic, Lipid lowering agents,
Anti-diabetic drugs, toxins and poisons

37. OCT
• Organic Cations across cell membrane
• Endogenous substrates:
Na+ , Histamine, Dopamine, NE, Uric Acid
• Drugs:
Diuretics, Quinine, Choline, Cimetidine etc.

38. SGLT
• Sodium Glucose Linked Transporter
• Renal Glucose reabsorption
• SGLT 2 – Use in Diabetes

40. MATE
• Multi-drug and Toxin Extrusion protein
• Bacteria – Cation transporters
• Metformin, Cimetidine, Topotecan

41. DRUG RESPONSE

42. Pharmacokinetics
• Absorption and distribution or excretion
• Protective barriers
• ABC transporters
BBB
Other tissues

43. • Hepatic transporters:
ABC
SLC
Supplementary to Hepatic Enzymes
• Renal Transporters:
Mainly SLC – OATP, OCT

44. Pharmacodynamics
• Clinical use: Drugs acting on brain
• SLC 1 and 6
• GABA, Glutamate, MAO, NE, 5HT,
Dopamine

45. Adverse Drug Response
• Control exposure of cell to foreign substances
• 3 categories
• Decreased uptake or secretion
• Enhanced uptake/reduced efflux
• Inhibition by drug
• Eg. Loperamide vs. Quinidine

46. Clinical Implications
• Targets for drug action
• Clinical studies focused on genetic variation in
membrane transporters
• Important in highly drug resistant cancers

47. Conclusion
• Drug development
• Lacunae in knowledge
• Further studies

48. Thank You!!