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Drug transporters Flashcards

1
Q

What are membrane transporters roles?

A
  • Regulate distribution and biovalailability of drugs
    -Remove toxic metabolites and xenobiotics
    -Protect haematopoietic stem cells from toxins
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2
Q

What does cellular membranes do to solutes?

A

Partition solutes to generate gradients through membrane transporters.

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3
Q

What is the function of membrane transporters?

A

Carry solutes across cell membranes which otherwise be impermeable to them
* Exploit gradients for various purposes (energy generation for example)

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4
Q

Mention an example of membrane transporters

A

F-type ATPase

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5
Q

Why are membrane transporters important?

A

Transporters play an important role in absorption, distribution and excretion, and as such are important in:
* Pharmacokinetics
* Pharmacodynamics
* Drug-drug interactions
* Toxicity
* Drug delivery
* Personalised healthcare (precision medicine)

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6
Q

Mention characteristics of transporter-targeting drugs

A
  • Currently all inhibitors
  • Usually derived initially from natural substrate
  • Suitable chemical modification to resist metabolism, maybe with ‘bulky’ substituents
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7
Q

How remove of toxic metabolites works?

A

-from the cells into urine, bile and the intestinal lumen
– out of the brain across the blood brain barrier

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8
Q

What do transporters influence in drug disposition?

A
  • Drug action
  • Drug metabolism
  • Drug resistance
    *
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9
Q

Mention the three major families of transporters

A
  1. P-type ATPases
  2. ATP – Binding Cassette (ABC) transporters
  3. SoLute Carrier (SLC) family members (2nd largest family)
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10
Q

Describe P-type ATPases

A
  • Ion pumps that use energy from ATP hydrolysis
  • Ubiquitous membrane proteins
    41 members, often heterodimeric (a and b)
  • Autophosphorylation of catalytic asp
    Hence P-type
  • Six subfamilies
    Five transport inorganic cations (probably)
  • Can be found on cell-surface and intracellular organelles
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11
Q

Describe ABC transporters

A
  • Ubiquitous membrane proteins
    48 in seven families A-G
  • Found in cell-surface and organellar
  • Utilise ATP hydrolysis to facilitate solute transport out of the cytosol
  • Mostly monomeric
    Individual subunits typically made up of two groups of nucleotide binding 6TM-spanning domains
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12
Q

Mention examples of multi-drug resistance drugs

A
  • ABCB1 (MDR1, pgp)
  • ABCC1 (MRP1)
  • ABCG2 (ABCP)
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13
Q

What is the function of multi-drug resistance drugs

A

Responsible for the efflux of a huge variety of exogenous compounds, notably chemotherapeutic agents
* reduces absorption at the apical membrane of epithelial cells

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14
Q

Depends of how the distribution of drugs across the membranes is needed we can define three types of transporters. Mention it the three types binding.

A

1.Pump
2.Carriers
3. Channels

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15
Q

Mention characteristics of ABC transporter structure

A
  • Mostly 12 TM domains, divided 6 and 6 (TMD1 and TMD2).
  • Nucleotide binding domain (liker between the two TMD1 and TMD2) there is where ATP binds. Generally exist as dimers.
  • N terminus is in cytoplasm and C terminus too.
  • Some could be only 6 TM domains, Some of them may be 18 TM domains.
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16
Q

Mention the 9 p-type ATPase subfamiles

A
  1. Phospholipid
  2. SERCA
  3. SPCA
    4.Na/K
    5.H/K
  4. PMCA
  5. Mn?
  6. Cu
    9.b subunits
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17
Q

Why are ABC transporters, active transporters?

A

They require energy in the form of ATP to
translocate substrates across cell membranes

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18
Q

How do ABC transporters work along with ATP to transport molecules

A

These proteins harness the energy of ATP binding &/or hydrolysis to drive conformational changes in the TMD and consequently transport molecules

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19
Q

Where is ABCB1 - P-glycoprotein expressed?

A

Expressed at brush border
membranes of enterocytes

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20
Q

What is the function of ABCB1 - P-glycoprotein

A

Functions as an efflux pump for
xenobiotics before they can access the
portal circulation

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21
Q

How do ABCB1 - P-glycoprotein affect cancer patients?

A

It is a frequent cause of treatment
failure in cancer patients

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22
Q

Mention examples of xenobiotic substrates of ABCG2 (BCRP) transporter?

A
  • Apigenin
    Dietary flavonoid
  • 5-Fluorouracil
    Anti-cancer
  • Mitoxantrone
    Anti-cancer
  • Tacrolimus
    Immunosuppressant
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23
Q

Mention examples of inhibitors of ABCG2 (BCRP) transporter?

A
  • Gefitinib - EGFR inhibitor
    Reverses drug resistance, increases cellular
    drug accumulation inhibiting ABCG2-mediated drug efflux
  • Febuxostat - XO inhibitor
    Treating gout
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24
Q

Which are the functions of ABC transporters?. Give an example of each function

A

1, Metabolic funtions
- Cholesterol export (ABCG2)
– Fatty acid metabolism (ABCD)
2. Signalling functions
- Prostaglandin, leukotriene (ABCC1) export
3. Ion movements
Cl-, HCO3
(CFTR, cystic fibrosis transmembrane
regulator) (important specific for this family due to is link to the disease cystic fibrosis which affects lungs)

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25
Q

Describe SLC transporters

A
  • Ubiquitous membrane proteins
  • Second largest family of membrane proteins
    – ~430 members in 65 families
  • Present on cell-surface and organellar
  • Limited sequence/structural homology
    – 6TM-13TM
  • Multiple orphans (~20 %)
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26
Q

What are the metabolic functions of SLC transporters

A

Amino acids (~25 %), fatty acids, peptides, sugars, nucleosides, bile acids, urea, vitamins, nucleotides (mitochondria)

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27
Q

Mention the best recognised ABC family members

A
  1. P-glycoprotein, P-gp – encoded by ABCB1, also known as MDR1
  2. CFTR : Cystic fibrosis transmembrane regulator
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28
Q

What are the signalling functions of SLC transporters?

Mention examples too

A
  • Amino acid transmitters (glutamate, glycine, GABA)
  • Amines (noradrenaline, adrenaline, 5HT, dopamine, ACh)
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29
Q

What are some of the ions that can be moved by SLC

A

Cu, Zn, Mg, Fe, PO4 3-, SO4 2- accumulation

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30
Q

Mention the two distinct domain for all ABC transporters

A
  1. The transmembrane (TM) domains.
  2. The nucleotide binding domain/s (NBD).
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31
Q

Mention the two distinct domain for all ABC transporters

A
  1. The transmembrane (TM) domains.
  2. The nucleotide binding domain/s (NBD).
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32
Q

Why there is complex pharmacology involved in ABC transporters?

A

They have multiple overlapping binding sites

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33
Q

Which is the biggest type of ABC transporters?

A

ABCA with 1200 to 2600 aas

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34
Q

What are the characteristics for the transmembrane (TM) domains of ABC transporters?

A
  1. a helices embedded in the membrane bilayer
  2. Recognise a variety of substrates
  3. Undergo conformational changes to transport the
    substrate across the membrane
  4. Variable sequence and architecture of TMDs reflects the chemical diversity of substrates that can be translocated
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35
Q

What are the characteristics for the nucleotide binding (NBD) transporters?

A

Its located in the cytoplasm and Highly conserved sequences

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36
Q

What type of compounds Influx ABC trasnporters transport?

A

Nutrients such as
-Maltaso
-Histidine
-Arabinose
-Galactosa

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37
Q

How are SLC transporters organized into families?

A

Based on 20 to 25% similarity

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38
Q

What is the usual nomenclature for the SLC transporters?

A

SLCnXm
* Where:
– SLC = root name, SoLute Carrier
– n = integer representing family (0-52)
– X = single letter denoting subfamily (A, B, C…)
– m = integer representing individual family member (isoform)

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39
Q

What does antiport or counter-transport means?

A

That two different molecules or ions are transported at the same time but in opposite directions
* One species is allowed to flow from high concentration to a
lower concentration (often Na+) while the other species is
transported simultaneously to the other side

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40
Q

Explain the ABC transporters mechanism of
transport (ATP-Switch model)

A

There are 2 principal NBDs conformations:
1. Formation of a closed dimer upon binding two ATP molecules
2. Dissociation to an open dimer facilitated by ATP hydrolysis and release of
inorganic phosphate (Pi) and adenosine diphosphate (ADP)

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41
Q

Mention an example of Na+/Ca2+ counter-transporters and how do they work

A

(NCX1-3/SLC8A1-3)
* Na+ binds to the transport carrier protein on its exterior side,
and Ca2+ bound to the same protein on the membranes interior
side
* Once both are bound, a conformational change occurs which
releases energy and the sodium ion is transported to the
interior and calcium to the exterior

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42
Q

What induce the conformational changes in the TMD ? What is the result of this conformational changes?

A

Switching between the open and closed dimer conformations induces
conformational changes in the TMD resulting in substrate translocation.

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43
Q

Where are Na+/Ca2+ counter-transporters found?

A

This transporter is situated on almost all cell membranes

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44
Q

Where ABCG2 are expressed?

A
  1. High expression in the brain
    2.Expression at apical membrane of renal & intestinal epithelial cells
  • Localized to canalicular membrane of hepatocytes
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45
Q

Mention the functions of ABCG2

A

Consist on excretion role
1. Restricts intestinal absorption of pharmaceuticals.
2. If its present in brain, placenta- Defence of organs against xenobiotics
3. Protects haematopoietic stem cells against haem-induced toxicity
4. Exports nutrients into milk
5. Exports urate from kidney
6. Exports chemotherapeutic drugs from cancer cell

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46
Q

Mention examples of symporters

A
  • Na+/amino acid co-transport
    – SLC1A glu/asp (EAAT) ala/ser/cys (ASCT)
    – SLC6A gly/pro/leu/met/iso/val/asn/phe/ala/ser/thr
    – Widely expressed, incl. gut epithelium
  • H+/amino acid co-transport
    – SLC15A di- and tri-peptides (PEPTs)
    – SLC36A (PATs)
    – Gut and kidney epithelia
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47
Q

Where are Solute Carrier Organic Anion (SLCO) transporters expressed?

A

In the liver: SLCO1B1, 1B3, 2B1 mainly located in sinusoidal membrane of hepatocytes

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48
Q

Which are the potential function of solute carrier (SLC) transporters?

A

SLC are potential to function as:
- Antiporters (exchanger)
– Symporters (co-transporters)
– Equilibrative transporters
– One family (SLC27) has enzymatic function
– Some are electrogenic - translocation of net charge across the
membrane (SLC1A7, cf. ion channels)

49
Q

What suggest that SLCs lack an ATP binding domain?

A

SLCs lack an ATP binding domain, so exploit ion gradients to facilitate solute transport.

50
Q

A polymorphism in which gene is associated with impaired transporter function?

A

SLCO1B1 gene

51
Q

Mention examples of SLCO1B1/OATP1B1 endogenous substrates

A

Cholic acid
PGE2
Thyroxine
17b-Estradiol glucuronide

52
Q

Name the three types of transport show in the image (export and import directions)

A
53
Q

Mention examples of SLCO1B1/OATP1B1 xenobiotic substrates

A
  • Rifampicin
    Antihypertensive
  • Atorvastatin
    Antihypercholesterolemic
  • Bosentan
    Antihypertensive
  • Enalapril
    Antihypertensive
54
Q

Explain the Neurotransmitter Transporters mechanism.

A
55
Q

Where is Solute Carrier Organic Anion (SLCO) SLCO1B3/OATP1B3 majorly expressed?

A
  • In the liver
  • Sodium-independent uptake of nonpolar drugs and hormones from the portal vein
56
Q

Which types of solutes SLC transport?

A

-Charged and uncharged organic molecules
– Inorganic molecules
– Gas ammonia

57
Q

What is the importance of SLCO1B3/OATP1B3

A

A critical role in bile acid and bilirubin
transport
– Mutations in this gene lead to Rotor syndrome hyperbilirubinemia (mild, rare)

58
Q

How SLC as a facilitative transporters work?

A
  • solutes flow down electrochemical gradients
59
Q

Describe the SLC22 family and where are they expressed

A

The SLC22 family of transporters is mostly composed of non-selective transporters, which are expressed highly in liver, kidney and intestine

60
Q

How SLC as a How SLC as a – Secondary active transporter work?

A

Solutes flow uphill against
electrochemical gradient by coupling to transport of second solute that flows down gradient, overall free energy change is still favourable

61
Q

Describe the membrane topology of SLC22

A

Membrane topology is predicted to contain 12 TM domains with intracellular termini, and an extended extracellular loop at TM 1/2

62
Q

Why are SLC22 important?

A
63
Q

How is SLC22 family divided?

A

The family may be divided into three subfamilies based on the nature of the substrate transported:
– organic cations (OCTs),
– organic anions (OATs) and
– organic zwiterrion/cations (OCTN)

64
Q

How Secondary active transport: symporters work?

A

Symport or co-transport means that a molecule is allowed to be transported from high to low concentration while
“pulling” another molecule with it from low to high
concentration

65
Q

Where Secondary active transport: symporters occurs?

A

These transporters occur especially through the epithelial cells of the intestinal tract and the renal tubules of the kidneys to enable absorption of substances into blood.

66
Q

Mention examples of SLC22A6/OAT1 xenobiotic substrates

A
  • p-Aminohippuric acid
    Diagnostic aid
  • Azidothymidine
    Antiretroviral
  • Simvastatin
    Antihypercholesterolemic
  • Telmisartan
    Antihypertensive
67
Q

Mention examples of SLC22A6/OAT1 inhibitor

A

Probenecid
Anti-gout
High potency, but non-selective

68
Q

Give an example of Secondary active transport: symporters.

A

Na+/glucose co-transporter (SGLT/SLC5A)

– On its exterior side the transport protein has 2 binding sites, one
for Na+ and one for glucose.

– When both are bound to the protein, there is a conformational
change allowing the electrochemical gradient to provide the energy needed to transport both of these molecules into the cell

69
Q

Mention examples of SLC22A2/OCT2 xenobiotic substrates

A
  • Amiloride
    Diuretic
  • Metformin
    Antidiabetic
  • Procainamide
    Local anaesthetic
  • Ranitidine
    Anti-ulcer
  • Varenicline
    Anti-craving
70
Q

Mention examples of SLC22A2/OCT2 inhibitor

A

Decynium-22

71
Q

Mention 3 SLC families transporters

A
  1. OATP - Organic Anion Transporting Polypeptides
  2. OAT - Organic Anion Transporters
  3. OCT - Organic Cation Transporters
72
Q

Where are mainly transporters expressed?

A

Many transporters expressed ubiquitously
Some demonstrate higher/selective expression in certain regions
(i.e liver, kidney)

73
Q

In which part of the small intestine are mostly transporters expressed?

A

Multiple transporters are expressed in the brush-border membranes of intestinal epithelial cells

74
Q

What is the purpose of transporters in the small intestine?

A

They are involved in the efficient absorption of nutrients or endogenous compounds

75
Q

Mention examples of influx transporters that are involved in improving absorption in the GI tract

A

PEPT1, OATP, ASBT

76
Q

Which transporter mediates the transport of peptide-like drugs?

Mention examples

A

PEPT1
* b-lactam antibiotics
* ACE inhibitors
* The dipeptide-like anticancer drug bestatin

77
Q

What is Pomaglumetad methionil

A

Pomaglumetad methionil – prodrug that is rapidly
absorbed and hydrolysed

78
Q

Where is OATP transporter present ? what are the some of the functions?

A

OATP present on the BBB,promote clearance through metabolism, transport a number of anti-cancer drugs.

79
Q

Give an example of OATP transporter inhibitor

A

Tyrosine kinase inhibitors reported to inhibit OATP (potential for DDIs!)
– Pazopanib and nilotinib have inhibitory potential towards OATP1B1
– Vandetanib has inhibitory activity towards OATP1B3

80
Q

What is OATP polymorphism associated?

A

OATP polymorphism is associated with the incidence of simvastatin myopathy.

81
Q

Which is the relation between OATP polymorphism and the inward sodium gradient?

A

SLC22/OAT are indirectly dependent on the inward sodium gradient, which
is a driving force for re-entry of dicarboxylates into the cytosol

82
Q

Where are OATPs expressed?

A

Through the body but they play a critical role in the liver

83
Q

Why are OATPs important?

A

Play critical roles in the absorption, distribution and excretion of xenobiotics

84
Q

Which OATPs are selectively expressed in the liver? What is its function?

A

OATP1B1 and 1B3 are selectively expressed in the liver, localized to the basolateral membrane of hepatocytes
* Facilitate access to intracellular targets/metabolic
enzymes

85
Q

Where are OATs expressed?

A

Throughout the body (kidneys important)

86
Q

Transporters demonstrate differential expression across the GI tract. Which is the major percentaje contribution transporter in the small intestine and colon?

A

Small intestine PEPT1 50%
Colon ABCC3 36%

87
Q

Which OATs are highly expressed in the kidney?

A

– OAT1 and OAT3 are highly expressed in the kidney, at the basolateral membrane of proximal tubules
– OAT4 expressed in kidney, at the apical membrane of proximal tubules

88
Q

Why are OATs important?

A

They have a role in drug excretion

89
Q

Where are ABCG2 expressed?

A
  • Expression is widespread
  • Presence on the luminal side of brain capillaries suggests a brain-to-blood transport direction
90
Q

What is the inducer of ABCG2?

A

PPARalpha

91
Q

Where are SLC9 Na+/H+ exchange (NHE) family expressed?

A

Transporters in liver & kidney

92
Q

What is the function of SLC9 Na+/H+ exchange (NHE) family Apical membrane of PCT cell

A
  • Transports 1 Na+ in and 1 H+ out
    Antiporter
  • Uses gradient established by Na+/K+ ATPase
  • Target of amiloride
  • Essential in maintaining blood pH at 7.4
93
Q

Where are this transporters ABCB1/P-gp and what is its function?

A

In the brain / drug exclusion

94
Q

Provided the role of Transporters in intestinal epithelium. Give an example

A

They are involved in the efficient absorption of nutrients or endogenous compounds

PEPT1 mediates the transport of peptide-like
drugs
– b-lactam antibiotics
– ACE inhibitors
– The dipeptide-like anticancer drug bestatin

95
Q

Which drugs may be affected by ABCB1/P-gp?

A

Anti-histamines (hH1R antagonists)
Hydroxyzine and Cetirizine

96
Q

Which tranporters are expressed in the brush-border membranes of intestinal epithelial cells?

A

-OATP
-PEPT1
-ASBT
-MCT1

97
Q

Provided an example of transporter in theintestinal epithelial for drug accumulation?

A

SLC15A1/PEPT1 and SLC36A1/PAT1
- Exploit H+ gradient
- Transport a range of substances, including:
– Di- and tripeptides (protein metabolites)
– 5-aminolevulinic acid
– Bacterial peptides (fMLP)

98
Q

Which is the relation between P-gp and absorption?

A

P-gp affects the absorption of many drugs because of its broad substrate specificity

99
Q

What are the role of efflux transporters in intestinal epithelium? Give 3 examples

A

The efflux transporters excrete substances into the lumen of the intestine, thus limiting net absorption.
eg.P-gp, MRP2, BCRP

100
Q

Which is the portion of solutes reabsorbed in the proximal convoluted
tubule in the kidney? Name the slutes reabsorbed

A

60 % of all solute
- Glucose and amino acids
* Bicarbonate
* Inorganic phosphate and water

101
Q

Give 3 transporters in liver & kidneyc vvc vc

A
101
Q

Give 3 transporters in liver & kidneyc vvc vc

A
102
Q

What are the OCTs transporters? Give 2 examples and where are those located?

A

Are multi-specific uptake transporters expressed in numerous epithelia
throughout the body.

OCT1
* Highly expressed in the liver, at basolateral
membrane of hepatocytes
– OCT2
* Highly expressed in kidney, at basolateral
membrane of distal convoluted tubules

103
Q

Explain the process of Na+/K+ ATPase transporter in the liver & kidney?

A

Primary active transporter.
Transports 3 Na+ out of cell (into interstitium)
and 2 K+
into cell whilst hydrolysing one
molecule of ATP
* Reabsorption of filtered Na+
* Generates/maintains electrochemical gradients
* Gradients used by other transporters

104
Q

Why is it important to understand drug-metabolizing enzymes ?

A

It allows the prediction of DDIs in vivo from in vitro data.

105
Q

What is the purpose of International Transporter Consortium (ITC) ?

A
  • To determine if a similar predictive perspective exists for drug transporter proteins
  • Comprises transporter experts from industry, academia and regulatory agencies
106
Q

What are some of the things that the FDA provides for New Drug Applications (NDA) and Biologic License applications (BLA)?

A

Provides recommendations for with in vitro and in vivo studies of drug metabolism, drug transport, and drug-drug or drug-therapeutic protein interactions
Focus on drug transport

107
Q

Indicate each process of the following image about drug transporters

A
108
Q

What has been documented in recent years by the FDA regarding transporters?

A
  • All investigational drugs should be evaluated in vitro to determine whether they are a potential substrate of P-gp or BCRP
  • Investigational drugs should be evaluated in vitro to determine whether they are a substrate of hepatic uptake transporters OATP1B1 or OATP1B3, when their hepatic pathway is significant
  • Similarly, investigational drugs should be evaluated in vitro to determine whether they are a substrate of OAT1 or OAT3 or OCT2 when renal active secretion is important

The need for further in vivo drug interaction studies will be based on in vitro evaluation

109
Q

How you can identify key transporters as relevant targets for DDI?

A

– Decision making flowcharts to identify substrates/inhibitors of transporters
– Recommendations on substrates and inhibitors
– Directions for essential in vivo DDI studies for transporters
– Unbound concentration of drug is more relevant for DDI predictions
– Use of validated in vitro transporter model

110
Q

What needs to be considered for therapeutic proteins according to FDA?

A

The potential for interactions with drug products

111
Q

What should include the development of a drug based on the FDA Guidance 2017?

A

– Identification of the principal routes of elimination
– Quantitation of the contribution by enzymes and
transporters to drug disposition
– Characterization of the mechanism of drug-drug
interactions
– in vitro drug transporter studies with and without
inhibitor or with and without expression of the
transporter

112
Q

What study needs to be conducted for cytokine and cytokine modulator investigational drugs?

A

Studies should be conducted to determine the TP’s effects on CYP enzymes or transporters.

113
Q

How can in vivo evaluations be done for therapeutic proteins?

A

The in vivo evaluations of TPs in targeted patient populations can be conducted with individual substrates for specific CYP enzymes and transporters, or studies can be conducted using a “cocktail approach”

114
Q

What are some common cell-base assays?

A
  • Uptake inhibition assays
  • Bidirectional and unidirectional transport assays
  • Cytotoxicity assays
    These assays utilize fully differentiated monolayers of mammalian cell lines to conduct a range of studies
115
Q

Which are the two different mechanisms where drug transporters may be involved in organ toxicity?

A
  1. Disruption of the transport function of controlling the influx and efflux of
    essential nutrients and ions
  2. Transporter regulation allowing intracellular drug concentrations to reach
    unsafe levels leading to organ- specific injuries
116
Q

What are some common membrane permeability and transport assays?

A

For transport assays and membrane permeability functions, cells are seeded onto semipermeable membrane support that develops into a monolayer resembling the physiological epithelial barrier in vivo
* Caco-2, Calu-3
Primary human epithelial cell lines

117
Q

What are the effects of altered transporter kinetics due to inhibition, saturation or genetic polymorphisms?

A

Altered transporter kinetics due to inhibition, saturation or genetic polymorphisms may significantly alter the systemic or organ level of drug exposure, and subsequently result in altered PK, PD and safety profiles.

DMPK (7 decks)

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