Drug Transporters

Question 1

What are the 4 most important solute carrier superfamily sub-families? What do they do?

Answer 1

1. OAT influx non ATP
2. OATP’’
3. OCT’’
4. MATE -efflux non ATP

Question 2

What are the 3 most important ATP binding Cassette superfamily sub-families?

Answer 2

1. P-gp/MDR1
2. BCRP
3. MRPs

Question 3

How does the OAT transport organic anions against a negative membrane potential?

Answer 3

1. link facilitated efflux of the counterion: Alpha-ketoglutarate
2. Concentration is maintained by Na/deoxy carboxylate co-transporter
3. Na/K+ ATPase
   * tertiary active transporter

Question 4

How do Methotrexate and NSAIDs interact?

Answer 4

NSAIDS are inhibitors of OAT1 trnasport activity

–>Methotraxate cant be taken up into the kidney and stays in the blood and leads to toxicity

Question 5

How does Probenecid prevent Cidefovir induced nephroxicity?

Answer 5

Probenecid prevents neurotoxicity by blocking OAT-1 dependent cidefovir uptake into the proximal tubules

Question 6

What is OATP transport?

Answer 6

electroneutral exchangers

-transports substrates in exchange for HCO3-

Question 7

Where do people have multiple SNP in OATP1B1 what does this influence?

Answer 7

-statin efficacy and systemic exposure

Question 8

What is a potent inhibitor of OATP1B1 and blocks statin uptake?

Answer 8

Cyclosporin

Question 9

What does OCT transport?

Answer 9

influx

• simple passive diffusion of substrates
• (Na+/H+ independent)

Question 10

What does MATE do?

Answer 10

-primarily responsible for secreting OCT-transport substrates

• renal tubular secretions of cationic drugs into the urine
• hepatic elimination of cationic drugs into bile

Question 11

How do SNPs of OCT and MATE affect metformin?

Answer 11

• metformin is very basic anti-diebetic drug that acts in the liver and is elimated unchged by renal tubule
• OCT/MATE SNP–> loss of transporter activity and decreased kidney uptake/excretion –increased systemic drug availability

Question 12

How does cimetidine affect OCT/MATE?

Answer 12

prevents renal elimination of other OCT dependent drugs

-such as procainamide–>increased plasma concentration of procainamide

Question 13

What is cisplatin coadministered with, why?

Answer 13

Cimetidine blocks cisplatin uptake into the kidney and prevents cisplatin induced nephrotoxicity

Question 14

What does Pgp/MDR1 transport?

Answer 14

bulky hydrophobic structures with neutral/positive charge
-specificity overlaps with CYP3A4

-inducers rifampin and st. johns wort—>decreased plasma concentraiton

Question 15

What happens when P-gp inhibitors such as cyclosporin are used with digoxin?

Answer 15

-decreased drug elimination–>toxicity

Question 16

What happens when P-gp inducers such as rifampicin and st johns wort are used with digoxin?

Answer 16

• increased drug efflux
• decreased concentration
• decreased efficacy

Question 17

What happens when loperamide a opioid receptor agonist is used in the treatment of diarrhea? What happens if you give it with cyclosporin?

Answer 17

potent substrate of P-gp therefore does not cross BB

-allows loperamide to cross BBB and enter CNS where it can cause respiratory depression

Question 18

Do cancer cells upregulate or down regulate expression of P-gp?

Answer 18

upregulate–increased efflux of anti-cancer drugs