The Pharmacology of Drug Transporters Flashcards
What promotes tissue-specific drug uptake and barrier functions?
Selective expression of transporters
If you have decreased uptake from plasma and or decreased efflux (clearance) in the liver/kidney, what will be the result?
decreased clearance, increased plama concentrations, increased target organ concentrations, and the potential for toxicity
if you have increased uptake and/or decreased efflux in the toxicological target organ, what will be the result?
increase in cellular concentration and increased toxicity
if you have a drug that inhibits the transport of endogenous transporter substrates, what will be the result?
increased plasma OR cell concentration of substrates/increased toxicity
How can drug transporters act as mediators of drug-drug interactions?
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
What are the two major classes of transporter proteins implicated in drug transport, and generally what kind of transporters are they?
Solute Carrier (SLC) superfamily - predominantly influx/uptake transporters
ATP-Binding cassette (ABC) superfamily - ATP-dependent efflux transporters
What are the 4 most important subfamilies of SLC transporters?
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
What are the 3 most important subfamilies of ABC transporters?
P-gp/MDR1 (P-glycoprotein/Multidrug resistance 1)
BCRP (breast cancer resistance protein)
MRPs (multidrug resistance proteins)
Discuss the mechanisms of OAT transporters
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!
Where are OATs predominantly expressed?
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
What endogenous substrates do OATs transport?
cGMP, bile salts, citric acid cycle intermediates, hormones
What are some important drugs that OATs transport?
Methotrexate (anti-cancer), NSAIDs, cidefovir (anti-viral)
What is the clinical significance of Methotrexate and NSAIDs in regards to OATs?
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
What is the clinical significance of probenicid and cidefovir in regards to OAT transporters?
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
discuss the characteristics of OATP transporters
uptake/influx transporters
electroneutral exhangers
transports substances in exchange for HCO3-
Where are OATPs expressed?
broadly - many tissues including gut, liver, kidney proximal tubules