The document discusses membrane transporters and their role in drug response. It begins with an overview of the major transporter superfamilies, ABC and SLC, describing their structure and function. It then examines the involvement of specific transporters in pharmacokinetic processes like hepatic and renal drug transport. The document also explores how transporters impact drug action in the brain and the relationship between transporters and both therapeutic and adverse drug responses.

1. Membrane Transporters In
Therapeutic And Adverse Drug
Response
-Dr Darsana S Kumar

2. OVERVIEW
 Introduction
 Basic Mechanisms of membrane transport
 ABC and SLC transporter superfamily
 Transporters involved in pharmacokinetics
Hepatic transporters and renal transporters
 Transporters and pharmacodynamics : Drug Action in the
brain
 Membrane transporters in therapeutic drug response
 Membrane transporters in adverse drug response
 Transporters in Regulatory Sciences

3. Introduction
Membrane transport proteins are present in all
They control the influx of essential nutrients and
and the efflux of cellular waste, environmental
drugs, and other xenobiotics
2000 genes in humans code for transporters or
transporter related proteins
Function may be facilitated or active
Two major super families  ABC and SLC

4. CHANNELS VERSUSTRANSPORTERS
CHANNELS
Two primary states, open and
closed
Open state act as pores for
selected ions flowing down an
electrochemical gradient.
Return to the closed state as a
function of time.
Potentiators (e.g., ivacaftor) may
increase the probability that a
channel is in open state.
TRANSPORTERS
Transporter forms an intermediate
complex with the substrate
(solute)
Conformational change in
transporter
Induces translocation of substrate to
other side of the membrane.
Transporter-mediated membrane
transport is characterized by
saturability and inhibition by
substrate analogue.

5. Basic Mechanisms of Membrane
Transport
I. Passive Diffusion
II. Facilitated Diffusion
III. Active Transport
IV. Vectorial transport

6. I. Passive transport
Partition from
aqueous to lipid phase
Diffusion across lipid
bilayer
Repartition into aqueous
phase on opposite side
Simple diffusion along electrochemical gradient

7. II. Facilitated diffusion
 Diffusion facilitated by a membrane transporter
 No energy required
 Occurs according to electrochemical gradient
 Examples : glucose, sodium ions, and potassium ions.

8. III . Active transport
 Transport of solutes against their electrochemical gradients with the use of
energy.
 Concentration of solutes on one side create potential energy
 An important role in the uptake and efflux of drugs and other solutes.
 Further divided into
 Primary active transport
 Secondary active transport

10. IV. Vectorial transport
 Asymmetrical transport across a monolayer of polarised cells
 Important in absorption of nutrients, drugs from intestine(from
lumen to blood)
 Hepatobiliary and urinary excretion of drugs(from blood to lumen)
 Efflux of drugs from brain via brain endothelial cells & choroid
plexus
 ABC transporters  unidirectional efflux
 SLC transporters  both influx and efflux

13. Transporter Superfamilies
I. ABC
II. SLC

14. I. SLC transporters
Facilitated and ion coupled secondary active transporters
52 SLC families with 395 transporters(SLC1-SLC52)
Serve as drug targets or in drug absorption and disposition

15. SLC superfamily
 Associated with genetic diseases
 Highly selective → transporters in SLC18 interact with monoamines
 SLC22 family broad range of chemically diverse substrates
 Physiological roles  transport of amino acids for protein synthesis,
absorption , distribution and elimination of drugs
 Pharmacologically  drug absorption, tissue distribution and drug –
drug interactions

16. SLC transporters
Channels,
facilitators
and
secondary
active
transporters
Substrates 
ionic, non-ionic
species,
xenobiotics and
drugs
Important to
pharmacokinetics
and
pharmacodynami
cs
Mechanism 
gated pore
mechanism
and rocker
switch
mechanism

18. SLC LINKED DISEASES
 Hypophosphatemic nephrolithiasis SLC 9
 Primary bile acid malabsorption SLC10
 Hereditary hemochromatosis SLC11
 Gitelman syndrome SLC 12
 Primary systemic Carnitine deficiency SLC22
 Type 1 Diabetes Mellitus  SLC30A8
 Inflammatory bowel Disease SLC22A4 & SLC22A

19. II. ABC PROTEINS
Primary active transporters
Rely on ATP hydrolysis to actively pump their substrates across membranes
7 Family(ABC A-ABC G)
ABC superfamily includes 49 genes.

20. ABC TRANSPORTERS
(adenosine triphosphate -binding cassette)
Best recognised transporters –Pgp encoded by ABCB1 & CFTR encoded by ABCC7.
ABC transporters have NBDs(nucleotide-binding domains) on the cytoplasmic side
that contain motifs which participate in binding and hydrolysis of ATP.
Crystal structures of all ABC transporters show two NBDs, which are in contact with
each other.

21. ABC superfamily
 Mutation in at least 13 of the genes contribute to human
genetic disorders.
 Pharmacological aspects- MDR, xenobiotic export from
healthy tissues.
 MDR1, MRP2 and BCRP  drug disposition.

22. i. Structure and mechanism

23. ii. TISSUE DISTRIBUTION OF ABC TRANSPORTERS
intestinal epithelia  pump out
xenobiotics,including many orally
administered drugs.
Vectorial transport  in polarized tissues
of kidney and liver.
Cell barriers  blood side of the
endothelial or epithelial cells restrict
entrance of toxic compounds into tissues:
• Blood brain barrier,
• Blood-CSF barrier ,
• Blood-testis barrier
• Blood-placenta barrier.

24. iii. PHYSIOLOGICAL ROLES OF ABCTRANSPORTERS
• Studies done in knockout animals or patients with genetic defects in these
transporters.
• Result : Complete absence of these drug-related ABC transporters is not lethal
• Inhibition of physiologically important ABC transporters (especiallythose related
directly to the genetic diseases) by drugs should be avoided to reduce the incidence
of drug-induced side effects.

25. iv. ABC TRANSPORTERS IN DRUGABSORPTION
AND ELIMINATION
 MDR1
 Rifampicin (MDR1 inducer)
 Systemic exposure of oral digoxin decreased.
 Quinidine, verapamil, spironolactone  MDR1 inhibitors
 Reduce the renal excretion of digoxin
 Drugs having narrow TI digoxin, cyclosporine, tacrolimus , can have MDR1
based drug-drug interactions.
 MRP3  sinusoidal efflux in liver of glucuronide conjugates
 Dysfunction of MRP3  shortens elimination t1/2

26. v. ABC LINKED HUMAN DISEASES
 Tangier disease (defect in cholesterol transport, ABCA1)
 Dubin-johnson syndrome (defect in biliary bilirubin glucuronide excretion,
MRP2)
 Pseudoxanthoma (unknown mechanism, ABCC6)
 Persistent hyperinsulinemia and hypoglycaemia of infancy ( defect of inwardly
K+ conducting regulation in pancreatic B cells, ABCC8)

27. Transporters Involved in Pharmacokinetics
I. Hepatic Transporters
II. Renal transporters
I. Organic cation transporters
II. Organic Anion Transporters

29. I. Hepatic Transporters
SLC TRANSPORTERS
Located in sinusoidal membrane of
hepatocytes.
Mediates hepatic uptake of organic
anions, cations, and bile salts.
Facilitated or SecondaryActive
mechanisms
OATPs (SLCO), OCTs (SLC22),
ABC
TRANSPORTERS
Bile canalicular membrane of
hepatocytes
Efflux (excretion) of drugs and their metabolites, bile
salts, and phospholipids from liver to bile.
Primary active transport.
MRP2, MDR1, BCRP, and MDR2

30. Examples of role of Hepatic transporters in drug- drug
interactions
a. HMG-CoA reductase inhibitors
 Statins  Substrates of hepatic uptake transporters
 Hepatic uptake transporters (OATP1B1) and efflux transporters(MRP2)
 Concentrates the drug in liver  lesser systemic adverse effects.
b. Gemfibrozil
 PPAR-α activator, cholesterol lowering agent
 Inhibit uptake of active hydroxyl forms of statins by OATP1B1
 Increases systemic toxicity of statins

31. c. IRANOTECAN(CPT-11)
 Potent anticancer drug
i.v CPT-11
carboxylesterase
SN-38(active metabolite)  conjugated with glucuronic acid
SN -38 & SN38 Glucuronide
Excreted into bile by MRP2 (enters GI tract and causes diarrhoea)
 Probenecid inhibits MRP2 mediated biliary excretion of SN38 & Its
Glucuronide

32. d. Bosentan
 Endothelin antagonist used for treatment of PAH
 Taken up in liver→OATP1,OATP1B3→metabolised by CYP2C9,
CYP3A4
 Transporter mediated hepatic uptake is determinant of Bosentan
elimination
 Inhibition of hepatic uptake by cyclosporine, rifampicin and
sildenafil affect its pharmacokinetics.
e. Temocapril
 Temocaprilat ( active metabolite) excreted both in bile and urine
 Even in pts with renal failure  plasma concentration remains
unchanged

33. II Renal transporters –
i. OCT
 Organic cations are secreted in the proximal tubule
 Endogenous compounds, xenobiotics, drugs and its
metabolites
 MATE family  organic cations from tubule cell to lumen
 OCTNS  carnitine reabsorption

35. ii. Organic anion transport
 Primary function  removal of xenobiotics from the body
 Substrates  weakly acidic drugs. Pravastatin, captopril,
penicillin
 OAT1, OAT2, OAT3, OAT4, URAT1

37. Transporters and pharmacodynamics: Drug
action in brain

38. cont
 Transporters involved in release and reuptake of neurotransmittors are
SLC1 and SLC6.
 Transporters in both families play roles in reuptake of GABA,
glutamate and the monoamine neurotransmitters NE, 5HT, and DA.
 Serve as pharmacologic targets for neuropsychiatric drugs.

39. contd
 SLC6 family members localized in the brain and are secondary
active transporters.
 Many of these transporters are present in other tissues (e.g.,
intestine, kidney, and platelets)
 Examples:
a. GABA Uptake: GAT1 (SLC6A1), GAT3 , (SLC6A11),GAT2 (SLC6A13)
b. Catecholamine Uptake: NET (SLC6A2)
c. Dopamine Uptake: DAT (SLC6A3)
d. Serotonin Uptake: SERT (SLC6A4)

40. a. GABA uptake –GAT1, GAT2, GAT3, BGT1
 GAT1-Most important GABA transporter in brain expressed in
GABAergic neurons
 Neocortex, cerebellum, basal ganglia
 GAT1  regulating the interaction of GABA at receptors
 GAT2  maintaining the homeostasis of GABA in CSF
 Tiagabine  inhibits reuptake of GABA by acting on GAT1

41. b. Catecholamine uptake
 NET  central and peripheral nervous tissues
 Reuptake of monoamine neurotransmitters &NE into neurons
 Drug target for antidepressant desipramine, TCAs and cocaine
 NET mutation  orthostatic intolerance

42. c. Dopamine uptake
 DAT located in dopaminergic neurons
 Dopamine reuptake
 Mood, behaviour, reward and cognition
 Cocaine, amphetamine interact with DAT

43. d. Serotonin Uptake (SLC6A4)
 Reuptake and clearance of 5HT in the brain
 Substrates  5HT, tryptoamine derivatives, neurotoxins and
fenfluramine
 Target of SSRI antidepressants amitriptyline
 Genetic variations behavioural and neurological disorders

44. Transporters In Therapeutic And
Adverse Drug Response

45. Membrane transporters in
Therapeutic drug responses
I. Pharmacokinetics
II. Pharmacodynamics
III. Drug resistance

46. I. Pharmacokinetics
 Transporters important in pharmacokinetics located
-Intestinal, renal, and hepatic epithelia
 Function-Selective absorption and elimination of endogenous
substances and xenobiotics
 Assists drug metabolizing enzymes in elimination
 Protective barrier function  Pgp in BBB protects CNS by efflux of
many drugs

48. II. Pharmacodynamics:
Transporters as Drug Targets
 SERT (SLC6A4) target SSRI
 Neurotransmitter reuptake transporters  TCAs, amphetamine,
anticonvulsants
 Inhibitor of the vesicular monoamine transporter VMAT2 (SLC18A2)
tetrabenazine  symptomatic treatment of Huntington disease
 Inhibition Na+-glucose transporters in the SLC5 family (SGLT1 and
SGLT2)  canagliflozin, dapagliflozin, empagliflozin→TX of T2DM

49. III. DRUG RESISTANCE
Membrane transporters play critical roles in the
development of resistance to anticancer drugs,
antiviral agents, and anticonvulsants.
• Decreased uptake of drugs.
• Enhanced efflux of hydrophobic drugs
• Overexpression of MRP4 (multi drug resistant
protein)
• Modulation of MDR1 expression and activity

50. Membrane transporters in Adverse
drug responses

51. ADVERSE DRUG RESPONSES
Transporters play crucial roles in the cellular activities and toxicities of chemical
carcinogens, environmental toxins and drugs.
I. Decreased uptake at clearance organs
II. Increased uptake at target Organs
III.Altered transport of endogenous
compounds at target organs
Transporter-
mediated adverse
drug responses can
be classified into
three categories

52. Example:
I. DECREASED UPTAKE AT CLEARANCE
ORGANS
oral
administration of
an HMG-CoA
reductase
inhibitor
Efficient first-
pass hepatic
uptake of the
drug by the SLC
OATP1B1
maximizes the
effects of such
drugs on hepatic
HMG-CoA
Reductase
Minimize adverse
effects in
systemic and
skeletal
myopathies

53. II. Increased uptake or decreased efflux at
target Organs
Loperamide (peripheral opioid) – substrate of
Pgp
Pgp prevents accumulation of Loperamide in CNS
Inhibition of Pgp–mediated efflux (Quinidine)in
the BBB
Increase in the concentration of Loperamide in
the CNS Respiratory depression
Eg. Loperamide-
quinidine
interaction

54. III. DRUGS MAY MODULATETRANSPORTERS
• Uptake: NTCP
• Excreted : BSEP
Bile Salts
• Uptake : OATP1B1
• Bilirubin glucoronide Excreted : MRP2
• Transported into blood : MRP3
Bilirubin
• Cholestasis or hyperbilirubinaemia
Inhibition of these
transporters

55. Transporters In Regulatory Sciences

56. cont
 Major determinants of variation in therapeutic and adverse drug reactions.
 Transporters may mediate drug-drug interactions that result in drug safety issues.
Example:
Gemfibrozil glucuronide formed in hepatocytes
Reduces the hepatic uptake and metabolism of cerivastatin
High Cp for cerivastatin Elevated statin levels
Statin-induced myopathies(rhabdomyolysis)

57. Cont.
U.S. FDA  issued clinical pharmacology guidance on performing drug-
drug interaction studies
If in vitro study  a new molecular entity (NME) inhibits the uptake of a
substrate of OCT2 at clinically relevant (unbound)concentrations.

58. To Summarize
 Basic Mechanisms of membrane transport
 ABC and SLC transporter superfamily
 Transporters involved in pharmacokinetics
 Hepatic transporters and renal transporters
 Transporters and pharmacodynamics: drug action in brain
 Membrane transporters in therapeutic drug response
 Membrane transporters in adverse drug response
 Transporters in Regulatory Sciences

59. Reference
 GOODMAN& GILMAN-13TH EDITION