Drug Transporters Flashcards
Which drug transporters are influx/uptake vs. efflux?
- Influx/uptake: OAT, OATP, OCT
- Efflux: MATE, P-gp/MDR1, MCRP, MRP
What is the substrate specificity of the OAT vs. OATP transporters?
- OAT: organic anions
- OATP: amphipathic organic anions >350 Da
What is the substrate specificity of the OCT transporter?
small organic cations
What is the substrate specificity of the MATE transporter?
organic cations
What is the substrate specificity of the P-gp/MDR1 transporter?
bulky hydrophobic structures with neutral or positive charge
What is the substrate specificity of the BCRP transporter?
neutral/negative compounds
What is the substrate specificity of the MRP transporter?
amphipathic molecules with at least 1 negative charge
Where are the ABC superfamily transporters heavily expressed?
BBB!
however, they are also expressed in the gut and liver
Which transporters belong to the ABC superfamily? Describe their ATP dependence.
P-gp/MDR1, BCRP, MRP; all are ATP-dependent
Which are the two ATP-INdependent drug transporters we talked about?
OATP and OCT
Which drug transporter utilizes tertiary active transport?
OAT
Which drug transporter utilizes secondary active transport?
MATE
What are the clinically relevant drug substrates of OAT transporters?
methotrexate, NSAIDs, and cidefovir
How do methotrexate and NSAIDs interact at OAT transporters?
NSAIDs are competitive inhibitors of the OAT1 transporter, thus blocking OAT1-dependent methotrexate uptake into the kidney (for excretion). Thus, methotrexate is not effectively eliminated, leading to increased plasma concentrations of methotrexate and increased toxicity.
How do probenecid and cidefovir interact at OAT transporters?
Probenecid is a potent inhibitor of OAT1, and cidefovir is a drug substrate transported into proximal tubules by OAT1. However, treatment with cidefovir is limited by severe renal toxicity. Thus, administering probenecid with cidefovir is an effective way of blocking uptake of cidefovir into the PTs and instead allowing it to be eliminated via glomerular filtration.
How does cimetidine affect interactions with drugs transported by the OCT class of transporters?
Cimetidine is a potent competitive inhibitor of OCT transporters, preventing renal elimination of important OCT-dependent drugs, like procainamide. This leads to an increased plasma concentration of procainamide (which has a narrow therapeutic window) and causes increased toxicity. In contrast, when cimetidine is co-administered with cisplatin, it blocks cisplatin uptake into the kidney, therefore preventing cisplatin-induced nephrotoxicity.
How does the OATP1B1 transporter influence the pharmacokinetics of the statin class of drugs?
It is responsible for the first pass effect of statins in the liver. Thus, it is important in the body’s response to statin (anti-cholesterol) drugs.
What is a well-known inhibitor of the OATP1B1 transporter, and what effect does this have?
cyclosporin; it blocks statin uptake in the liver, leading to decreased efficacy and increased risk of toxicity
Which drug transporter is an electroneutral exchanger?
OATP - transports organic anions in exchange for bicarb
Which transporter is important in the response to Statin drugs?
OATP1B1
What are the OATP1B1 polymorphisms that affect statin efficacy and systemic exposure?
OATP1B15 and OATP1B115; both decrease transporter activity, resulting in decreased statin uptake (therefore decreased efficacy) and increased systemic statin exposure (therefore increased toxicity)
Which drug transporter mediates simple passive facilitated diffusion of substrates?
OCT
Which drug is a potent competitive inhibitor of OCT transporters?
cimetidine
How does cyclosporin affect the pharmacokinetics of drugs that are substrates for the P-gp/MDR1 drug transporter?
- inhibitor
- leads to decr. efflux of P-gp substrates from liver
- increased systemic drug bioavailability
- increased risk of toxicity
How does St. John’s Wort affect the pharmacokinetics of drugs that are substrates for the P-gp/MDR1 drug transporter?
- inducer
- leads to incr. efflux of P-gp substrates from gut/kidney/liver
- decreased systemic drug bioavailability/plasma conc.
- decreased drug efficacy
How does rifampicin affect the pharmacokinetics of drugs that are substrates for the P-gp/MDR1 drug transporter?
- inducer
- leads to incr. efflux of P-gp substrates from gut/kidney/liver
- decreased systemic drug bioavailability/plasma conc.
- decreased drug efficacy
Describe the role of P-gp/MDR1 in determining the responsiveness of tumor cells to chemotherapeutic drugs.
- tumor cells often upregulate expression of P-gp/MDR1
- promotes efflux of anti-cancer drugs
- more aggressive cancer phenotype, poorer prognosis, decr. sensitivity to chemo drugs
