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Pharm Block 1 > The Pharmacology of Drug Transporters > Flashcards

The Pharmacology of Drug Transporters Flashcards

1
Q

What promotes tissue-specific drug uptake and barrier functions?

A

Selective expression of transporters

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2
Q

If you have decreased uptake from plasma and or decreased efflux (clearance) in the liver/kidney, what will be the result?

A

decreased clearance, increased plama concentrations, increased target organ concentrations, and the potential for toxicity

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3
Q

if you have increased uptake and/or decreased efflux in the toxicological target organ, what will be the result?

A

increase in cellular concentration and increased toxicity

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4
Q

if you have a drug that inhibits the transport of endogenous transporter substrates, what will be the result?

A

increased plasma OR cell concentration of substrates/increased toxicity

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5
Q

How can drug transporters act as mediators of drug-drug interactions?

A

If a drug can act as the substrate or inhibitor of another drugs transporter, it can reduce the efficacy of that drug due to decreased uptake, leading to an increase in plasma concentration of that drug

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6
Q

What are the two major classes of transporter proteins implicated in drug transport, and generally what kind of transporters are they?

A

Solute Carrier (SLC) superfamily - predominantly influx/uptake transporters

ATP-Binding cassette (ABC) superfamily - ATP-dependent efflux transporters

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7
Q

What are the 4 most important subfamilies of SLC transporters?

A

OAT (organic anion transporters)

OATP (organic anion transporting polypeptides)

OTC (organic cation transporters)

MATE*(multi-drug and toxin extrusion transporters)
*MATE is an efflux transporter, and is non-ATP-dependent

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8
Q

What are the 3 most important subfamilies of ABC transporters?

A

P-gp/MDR1 (P-glycoprotein/Multidrug resistance 1)

BCRP (breast cancer resistance protein)

MRPs (multidrug resistance proteins)

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9
Q

Discuss the mechanisms of OAT transporters

A

uptake transporter that transports organic anions against a negative membrane potential by linking to the facilitated efflux of alpha-ketoglutarate

alpha-ketoglutarate’s intracellular concentration is maintained by the Na/dicarboxylate co-transporter acting in concert with the Na/K ATPase

Thus this is tertiary active transport!

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10
Q

Where are OATs predominantly expressed?

A

liver and kidney proximal tubules

OAT1-3 on the basolateral kidney tubule cells

OAT4 on the apical kidney tubule cells

OAT2 on the basolateral liver cells

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11
Q

What endogenous substrates do OATs transport?

A

cGMP, bile salts, citric acid cycle intermediates, hormones

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12
Q

What are some important drugs that OATs transport?

A

Methotrexate (anti-cancer), NSAIDs, cidefovir (anti-viral)

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13
Q

What is the clinical significance of Methotrexate and NSAIDs in regards to OATs?

A

Methotrexate is eliminated via renal tubular elimination, and NSAIDs are inhibitors of OAT1 transporter activity

thus less methotrexate elimination and an increase in plasma methotrexate

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14
Q

What is the clinical significance of probenicid and cidefovir in regards to OAT transporters?

A

the treatment with cidefovir is limited as it causes severe renal toxicity - it is transported into proximal tubule cells by OAT1. Probenecid is a potent inhibitor of OAT1, and thus when co-administered, the elimination of cidefovir will be via glomerular filtration rather than across the renal epithelium

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15
Q

discuss the characteristics of OATP transporters

A

uptake/influx transporters

electroneutral exhangers

transports substances in exchange for HCO3-

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16
Q

Where are OATPs expressed?

A

broadly - many tissues including gut, liver, kidney proximal tubules

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17
Q

What are some important drugs that OATPs transport?

A

Statins

18
Q

What is an important inhibitor of OATPs?

A

Cyclosporin

19
Q

What is the clinical significance of OATP transporters?

A

their are multiple SNP in OATP1B1 that can decrease transporter activity (decreased statin uptake, decreased statin efficacy, increased systemic statin exposure, increased statin toxicity)

cyclosporin inhibits OATP1B1, resulting in decreased statin uptake - decreased efficacy, increased risk of toxicity

20
Q

Discuss the characteristics of OCTs

A

Uptake/influx transporters that mediate simple passive facilitated diffusion of substrates (Na, H - independent)

21
Q

Where are OCTs expressed?

A

gut, kidney, liver, others

22
Q

What do OCTs transport?

A

small positively charged compounds

23
Q

What are some important drugs that OCTs transport?

A

Cisplatin (chemo), metformin (anti-diabetes), cimetidine (H2 receptor antagonist), procainamide (antiarrhythmic, narrow therapeutic window)

24
Q

Discuss the characteristics of MATEs

A

Organic cation/proton antiporter

secondary active transport driven by H+ antiport

major role in the excretion of positively charged drugs

primarily responsible for the secretion of OCT transported substrates (typically coexpressed with OCTs, not OATs)

25
Q

Where are MATEs expressed?

A

liver and kidney

26
Q

What are MATEs responsible for?

A

renal tubular secretion of cationic drugs into urine

hepatic elimination of cationic drugs into bile

27
Q

What is the result of OCT/MATE SNPs?

A

loss of transporter activity –> decreased kidney uptake/excretion –> increased systemic drug availability

28
Q

What are most drug interactions mediated by OCT/MATE caused by?

A

Cimetidine

29
Q

What does cimetidine do?

A

prevents renal elimination of other OCT dependent drugs

30
Q

How can we use cimetidine to our advantage

A

coadminister with cisplatin, which will block cisplatin uptake into the kidney and prevent cisplatin-induced nephrotoxicity

31
Q

What kind of transporters are ABC transporters?

A

Active transport efflux transporter

32
Q

WHere are ABC transporters found?

A

apical luminal brush border membranes of gut, liver, kidney epithelia

endothelial cells of the BBB

upregulated in certain cancers

33
Q

What are some important drugs that P-gp/MDR-1 transport?

A

Digoxin, Loperamide

34
Q

What inhibits MDR-1?

A

Cyclosporin

35
Q

What induces MDR-1?

A

Rifampin, St. John’s wort (resulting in increased drug efflux and a decrease in plasma concentration)

36
Q

Where are BCRP transporters found?

A

gut enterocytes, liver, BBB, mammary epithelium

37
Q

What is an important drug the BCRPs transport?

A

Statins

38
Q

What are some endogenous substrates that MRPs transport?

A

glutathione, glucuronide, sulfate-conjugates

39
Q

What transporters form the BBB?

A

P-gp/MRP/BCRP ABC family efflux pumps form a barrier to a large range of drugs and other compounds by actively transporting these compounds back into the blood and thereby preventing their entry into the CNS

40
Q

What inhibits P-gp/MDR1?

A

cyclosporin

41
Q

What induces P-gp?

A

Rifampin, St. John’s Wor

42
Q

What is an effect of P-gp inhibitors on the BBB?

A

P-gp inhibitors (cyclosporin) can allow some drugs that are substrates for P-gp access to the CNS

Pharm Block 1 (8 decks)

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