Pharmacology of drug transporters Flashcards
what is the significance of drug transporters in the drug response (list)
- tissue expression
- expression levels
- activity
- polymorphisms
- inhibitors
2 ways to prevent a drug from getting into a tissue
- lack transporter for drug
- have an influx transporter for the drug with many more efflux transporters that immediately pump the drug out
3 ways that drug transporters can cause toxicity
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
Solute carrier (SLC) superfamily transporters
- 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)
types of ATP-binding Cassette (ABC) superfamily
- P-gp/MDR1: P-glycoprotein/multidrug resistance 1
- BCRP: Breast cancer resistance protein
- MRPs: multidrug resistance proteins
how is the intracellular concentration of alpha-ketoglutarate maintained?
-Na/deoxycarboxylate co-transporter acting in concert with Na+/K+ ATPase
endogenous use of OAT
-cGMP, bile salts, Citric acid cycle intermediates, hormones
drugs using OAT
-methotrexate (anti-cancer), NSAIDs, and cidefovir (anti-viral)
endogenous things transported by OATP
-bile acids, steroids, thyroid hormones
drugs transported by OATP
-statins
endogenous things transported by OCT
monoamine nts, creatinine, catecholamines
what is the main difference between OCT and MATE?
OCT transports things plama to cell and MATE transports things from cell to lumen
MATE is responsible for…
- renal tubular secretion of cationic drugs into urine
- hepatic elimination of cationic drugs into bile
OCT/MATE polymorphisms
- 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
characteristics of ATP binding Casette family of transporters
- 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
Breast cancer resistant protein (BCRP)
- 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)
multidrug resistant proteins (MRP)
- substrates: amphipathic molecules with at least one neg charge
- endogenous substrates: glutathione, glucoronide, and sulfate conjugates
- drugs: anthracyclines, vinca alkaloids, etoposide, vincristine, methotrexate, antivirals
blood brain barrier
- 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
