Drug Transporters Flashcards
What happens when there is a decrease in the uptake or the efflux of drug in the liver or kidney?
It will lead to increased plasma concentration of the drug which can lead to increased toxicity.
What happens where there is an increase in the uptake and a decrease in the efflux in the target organ for the drug?
It will lead to increased concentration of drug in the target organ and increased toxicity.
What happens when there is an inhibition of transport of drugs?
The concentration in the blood will be increased which can lead to increased toxicity.
How do drug-drug reactions impact transport?
Drug B can block a transporter for Drug A, causing Drug A to build up in the plasma and so the high concentration of Drug A can lead to toxicity and/or decrease the efficacy of the drug as it isn’t reaching the target organ.
What are the transporters of the solute carrier superfamily (SLC)?
OAT
OATP
OCT
MATE
What are the transporters of the ATP-binding cassette superfamily (ABC)?
P-gp/MDR1
BCRP
MRP
OAT
Organic Anion Transporter
How does OAT transport?
Uptake
Antiports an organic anion and a-ketoglutarate
Where is OAT found?
Liver
PT of kidney
What does OAT transport?
Low MW organic anions
How does methotrexate and NSAIDs interact with OAT?
NSAIDs block the activity of OAT and methotrexate cannot be taken into the kidney leading to methotrexate toxicity
How is probenecid used with cidefovir and OAT?
Probenecid prevents Cidefovir renal uptake which blocks cidefovir-induced nephrotoxicity
OATP
Organic Anion Transporter Polypeptides
How does OATP transport?
Antiprotons organic anion and HCO3-
Where is OATP found?
Gut
Liver
Kidney PT
What does OATP transport?
Uptake
Amphipathic anions of MW > 350 Da
What are the problems with OATP SNPs and statins?
Some OATP polymorphisms lead to decreased statin transport which reduces their efficacy and increases their toxicity
What is the effect of cyclosporin on OATP and statins?
Cyclosporin block OATP, which blocks STATIN uptake and causes STATIN toxicity
OCT
Organic Cation Transporter
How does OCT transport?
Uptake
Simple facilitated diffusion of organic cations
Where is OCT found?
Gut
Liver
Kidney
What does OCT transport?
Small cations
MATE
Multidrug and Toxin Extrusion Transporter
How does MATE transport?
Efflux
Antiports H+ and cationic drugs
Where is MATE found?
Liver
Kidney
What does MATE transport?
Main role is in secretion of the OCT substrates
What can SNPs of OCT/MATE cause?
It can cause the loss of either of these transporter’s activities which will lead to increased drug toxicity
How does cimetidine affect OCT/MATE and procainamide?
Cimetidine blocks OCT-mediated renal uptake of many drugs like procainaminde which blocks their elimination and increases their plasma concentration
How does cimetidine affect OCT/MATE and cisplatin?
Cimetidine blocks OCT uptake of cisplatin and prevents the nephrotoxic effects of cisplatin
P-gp/MRD1
P-glycoprotein/Multidrug Resistant Protein 1
How does P-gp/MRD1 transport?
Efflux
Active Transport
Where is P-gp/MRD1 found?
Intestine
Kidney
Liver
What does P-gp/MRD1 transport?
Bulky hydrophobic neutral or positively charged molecules
How does cyclosporin affect P-gp/MRD1 and digoxin?
Cyclosporin inhibits P-gp-mediated elimination of digoxin which increases availability and toxicity as digoxin has a narrow therapeutic range
How do rifampicin and St. John’s Wort affect P-gp?
Both induce Pg-p and will lead to increased drug efflux, leading to decreased drug efficacy
How does cyclosporin affect loperamide and P-gp?
Cyclosporin inhibits P-gp, which will enhance CNS accessibility by overcoming BBB and allow loperamide to pass the BBB and enter the CNS leading to respiratory depression
How do tumor cells use P-gp?
Tumor cells up regulate P-gp by up regulating it which allow them to have high efflux of anti-cancer drugs
BCRP
Breast Cancer Resistant Protein
What is the general function of BCRP?
Concentrates breast milk
Where is BCRP found?
Breast
Gut
Liver
BBB
What does BCRP transport?
Transports neutral and negatively charged compounds like statins
MRP
Multidrug Resistant Protein
Where is MRP found?
Many tissues
What does MRP transport?
Transports positive amphipathic molecules
How is the BBB maintained?
It is maintained via an ABC transporter that actively pumps compounds like drugs out to the blood and keeps them out of the CNS.
