Drug Transporters

Question 1

Which drug transporters are influx/uptake vs. efflux?

Answer 1

• Influx/uptake: OAT, OATP, OCT

- Efflux: MATE, P-gp/MDR1, MCRP, MRP

Question 2

What is the substrate specificity of the OAT vs. OATP transporters?

Answer 2

• OAT: organic anions

- OATP: amphipathic organic anions >350 Da

Question 3

What is the substrate specificity of the OCT transporter?

Answer 3

small organic cations

Question 4

What is the substrate specificity of the MATE transporter?

Answer 4

organic cations

Question 5

What is the substrate specificity of the P-gp/MDR1 transporter?

Answer 5

bulky hydrophobic structures with neutral or positive charge

Question 6

What is the substrate specificity of the BCRP transporter?

Answer 6

neutral/negative compounds

Question 7

What is the substrate specificity of the MRP transporter?

Answer 7

amphipathic molecules with at least 1 negative charge

Question 8

Where are the ABC superfamily transporters heavily expressed?

Answer 8

BBB!

however, they are also expressed in the gut and liver

Question 9

Which transporters belong to the ABC superfamily? Describe their ATP dependence.

Answer 9

P-gp/MDR1, BCRP, MRP; all are ATP-dependent

Question 10

Which are the two ATP-INdependent drug transporters we talked about?

Answer 10

OATP and OCT

Question 11

Which drug transporter utilizes tertiary active transport?

Answer 11

OAT

Question 12

Which drug transporter utilizes secondary active transport?

Answer 12

MATE

Question 13

What are the clinically relevant drug substrates of OAT transporters?

Answer 13

methotrexate, NSAIDs, and cidefovir

Question 14

How do methotrexate and NSAIDs interact at OAT transporters?

Answer 14

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.

Question 15

How do probenecid and cidefovir interact at OAT transporters?

Answer 15

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.

Question 16

How does cimetidine affect interactions with drugs transported by the OCT class of transporters?

Answer 16

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.

Question 17

How does the OATP1B1 transporter influence the pharmacokinetics of the statin class of drugs?

Answer 17

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.

Question 18

What is a well-known inhibitor of the OATP1B1 transporter, and what effect does this have?

Answer 18

cyclosporin; it blocks statin uptake in the liver, leading to decreased efficacy and increased risk of toxicity

Question 19

Which drug transporter is an electroneutral exchanger?

Answer 19

OATP - transports organic anions in exchange for bicarb

Question 20

Which transporter is important in the response to Statin drugs?

Answer 20

OATP1B1

Question 21

What are the OATP1B1 polymorphisms that affect statin efficacy and systemic exposure?

Answer 21

OATP1B15 and OATP1B115; both decrease transporter activity, resulting in decreased statin uptake (therefore decreased efficacy) and increased systemic statin exposure (therefore increased toxicity)

Question 22

Which drug transporter mediates simple passive facilitated diffusion of substrates?

Answer 22

OCT

Question 23

Which drug is a potent competitive inhibitor of OCT transporters?

Answer 23

cimetidine

Question 24

How does cyclosporin affect the pharmacokinetics of drugs that are substrates for the P-gp/MDR1 drug transporter?

Answer 24

• inhibitor
• leads to decr. efflux of P-gp substrates from liver
• increased systemic drug bioavailability
• increased risk of toxicity

Question 25

How does St. John’s Wort affect the pharmacokinetics of drugs that are substrates for the P-gp/MDR1 drug transporter?

Answer 25

• inducer
• leads to incr. efflux of P-gp substrates from gut/kidney/liver
• decreased systemic drug bioavailability/plasma conc.
• decreased drug efficacy

Question 26

How does rifampicin affect the pharmacokinetics of drugs that are substrates for the P-gp/MDR1 drug transporter?

Answer 26

• inducer
• leads to incr. efflux of P-gp substrates from gut/kidney/liver
• decreased systemic drug bioavailability/plasma conc.
• decreased drug efficacy

Question 27

Describe the role of P-gp/MDR1 in determining the responsiveness of tumor cells to chemotherapeutic drugs.

Answer 27

• 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