Pharmacology of drug transporters

Question 1

what is the significance of drug transporters in the drug response (list)

Answer 1

• tissue expression
• expression levels
• activity
• polymorphisms
• inhibitors

Question 2

2 ways to prevent a drug from getting into a tissue

Answer 2

• lack transporter for drug

- have an influx transporter for the drug with many more efflux transporters that immediately pump the drug out

Question 3

3 ways that drug transporters can cause toxicity

Answer 3

1) decr uptake and/or decr efflux in liver or kidney
2) incr uptake and/or decr efflux in target organ
3) drug inhibits transport of endogenous transporter substrates so their conc incr in the cells and get toxicity

Question 4

Solute carrier (SLC) superfamily transporters

Answer 4

• predominantly Influx/Uptake transporters
• OAT: Organic Anion Transporters
• OATP: Organic anion transporting polypeptides
• OCT: Organic cation transporters
• :MATE : multi-drug and toxin extrusion transporters (this is an efflux and non-ATP dependent transporter)

Question 5

types of ATP-binding Cassette (ABC) superfamily

Answer 5

• P-gp/MDR1: P-glycoprotein/multidrug resistance 1
• BCRP: Breast cancer resistance protein
• MRPs: multidrug resistance proteins

Question 6

how is the intracellular concentration of alpha-ketoglutarate maintained?

Answer 6

-Na/deoxycarboxylate co-transporter acting in concert with Na+/K+ ATPase

Question 7

endogenous use of OAT

Answer 7

-cGMP, bile salts, Citric acid cycle intermediates, hormones

Question 8

drugs using OAT

Answer 8

-methotrexate (anti-cancer), NSAIDs, and cidefovir (anti-viral)

Question 9

endogenous things transported by OATP

Answer 9

-bile acids, steroids, thyroid hormones

Question 10

drugs transported by OATP

Answer 10

-statins

Question 11

endogenous things transported by OCT

Answer 11

monoamine nts, creatinine, catecholamines

Question 12

what is the main difference between OCT and MATE?

Answer 12

OCT transports things plama to cell and MATE transports things from cell to lumen

Question 13

MATE is responsible for…

Answer 13

• renal tubular secretion of cationic drugs into urine

- hepatic elimination of cationic drugs into bile

Question 14

OCT/MATE polymorphisms

Answer 14

• there are mulitple polymorphisms that affect their activity
• influence the PK of mulitple organic cation drugs - especially metformin
• polymorphisms that decr tranporter activity can incr systemic drug availability

Question 15

characteristics of ATP binding Casette family of transporters

Answer 15

• active transport efflux transporters using ATP hydrolysis
• present on the apical luminal brush border mbs of gut, liver and kidney
• on endothelial cells of BBB- prevent access of drugs here
• upregulated in certain cancer cells- resistance to chemo

Question 16

Breast cancer resistant protein (BCRP)

Answer 16

• substrates: neutral/neg charge compounds
• endogenous: riboflavin (B12) - BCRP responsible for concentrating it in breast milk
• drugs: statins, antibiotics, etoposide, imatinib, and gefitinib (anti-cancer drugs)

Question 17

multidrug resistant proteins (MRP)

Answer 17

• substrates: amphipathic molecules with at least one neg charge
• endogenous substrates: glutathione, glucoronide, and sulfate conjugates
• drugs: anthracyclines, vinca alkaloids, etoposide, vincristine, methotrexate, antivirals

Question 18

blood brain barrier

Answer 18

• tight junctions prevent ions and large molecules passing between endothelial cells
• 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
• excludes most drugs other than those small and lipophilic