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Flashcards in Drug Transporters Deck (24):
1

Describe the mechanisms by which drug transporter proteins contribute toward transport of drugs across biological membranes.

- balance influx and efflux
- determine plasma drug concentration by mediating distribution, efficacy, and toxicity
- affected by tissue expression, activity, polymorphisms, and inhibitors

2

Describe carrier-mediated drug transport.

- cargo binds to transporter => conformational change => cargo released on other side of membrane
- saturable
- reversible depending on concentration gradient
- similar to enzyme kinetics; rate determined by michaelis-menten
- can be inhibited by other compounds

3

Describe the mechanisms by which drug transporters can contribute toward drug-induced adverse effects.

LIVER/KIDNEY
- increased efflux or decreased uptake => decreased total clearance => drug builds up in plasma and target tissue => toxicity

TOXICOLOGICAL ORGANS/BRAIN
- decreased efflux or increased uptake => increases exposure to drug in these tissues => increased concentration in target organ => toxicity

INHIBITION OF ENDOGENOUS SUBSTANCE UPTAKE
- drug acts as inhibitor of transporter that moves endogenous compound => endogenous buildup in plasma or cell => toxicity

4

Describe the mechanisms by which drug transporters can contribute towards drug-drug interactions.

If Drug #2 is a substrate or inhibitor of Drug #1's transporter...=> Drug #2 binds to the transporter => Drug #1 cannot be taken up => Drug #1 builds up in plasma => toxicity

5

What are the 2 main drug transporter families? List the 7 subfamilies.

SOLUTE CARRIER SUPERFAMILY (influx, non-ATP efflux)
- OAT (organic anion transporters)
- OATP (organic anion transporting polypeptides)
- OCT (organic cation transporters)
- MATE (multi-drug and toxin effusion transporters)

ATP-BINDING CASSETTE (ABC) SUPERFAMILY (ATP-dependent efflux)
- P-gp/MDR1 (p-glycoprotein/multi-drug resistance 1)
- BCRP (breast cancer resistant protein)
- MRPs (multidrug resistance proteins)

6

Describe the mechanism by which probenecid contributes towards interactions with drugs transported by OAT class of drug transporters.

- cidefovir is used to treat CMV retinitis, but is limited by severe renal toxicity (transported by renal OAT1)
- probenecid is an inhibitor of OAT1, blocks cidefovir uptake into proximal tubule cells => allows elimination
- probenecid and cidefovir are always administered together

7

Describe the role of the OATP1B1 transporter in influencing the pharmacokinetics of the statin class of drugs.

- role: statin uptake into liver cells
- polymorphisms OATP1B1*5 and OATP1B1*15 have decreased transport activity => decreased uptake into liver => bypasses first pass => decreased efficacy => increased systemic concentrations of statins => toxicity
- cyclosporins block OATP1B1 => increased systemic concentrations of statins => toxicity

8

Describe the mechanism by which cimetidine contributes towards interactions with drugs transported by the OCT class of drug transporters.

cimetidine is an H2 receptor antagonist used to treat acid peptic disorder
- extensively eliminated in the kidney
- prevents renal elimination of other OCT drugs

ex: blocks OCT => procainamide cannot be eliminated => increased serum levels

9

Describe the role of ATP-binding transporters in contributing towards the integrity of the BBB.

prevent entry into CNS by effluxing a lot of drugs back into the blood
- only allows small lipophilic drugs to enter BBB

10

Describe the effects of cyclosporin, rifampicin, and St. John's Wart on the pharmacokinetics of drugs that are substrates for the P-glycoprotein/MDR1 drug transporter and discuss the underlying mechanisms.

CYCLOSPORIN - P-gp/MDR1 inhibitor
#1 => decreased drug elimination => increased systemic availability => toxicity
#2 => decreases integrity of BBB by inhibiting p-gp and allowing drugs (loperamide) to cross BBB => respiratory distress

RIFAMPICIN/ST.JOHN'S WART - P-gp/MDR1 inducer
=> increased expression of P-gp/MDR1 => increased drug efflux => decreased plasma concentration => decreased drug efficacy

11

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

- upregulate P-gp/MDR1
- associated with poor

12

Describe the following features for OCTs:
- type
- substrate
- prototypical drugs
- inhibitors
- clinical significance/drug interactions

Type - influx, passive facilitated diffusion
Substrate - small cations
Drugs - cimetidine, cisplatin, metformin, procainamide
Inhibitors - cimetidine
Clinical Significance/Drug Interactions
- cimetidine blocks OCT renal uptake of many drugs => increased plasma concentration
- cimetidine blocks OCT renal uptake of cisplatin => prevents cisplatin induced nephrotoxicity

13

Describe the following features for MATEs:
- type
- substrate
- prototypical drugs
- inhibitors
- clinical significance/drug interactions

Type - non-ATP efflux, proton exchanger
Substrate - small cations
Drugs - cimetidine, cisplatin, metformin, procainamide
Inhibitors - cimetidine
Clinical Significance/Drug Interactions
- cimetidine blocks OCT renal uptake of many drugs => increased plasma concentration
- cimetidine blocks OCT renal uptake of cisplatin => prevents cisplatin induced nephrotoxicity

14

Describe the following features for P-gps:
- type
- substrate
- prototypical drugs
- inhibitors
- clinical significance/drug interactions

Type - ATP efflux, active transporter
Substrate - broad specificity, bulky hydrophobic, neutral or (+) charge
Drugs - digoxin, loperamide, etoposide
Inhibitors - cyclosporin, verapamil
Clinical Significance/Drug Interactions
- cyclosporin inhibits p-gp mediated elimination of digoxin => increased systemic availability
- st. john's wart/rifampicin induce p-gp expression => increased efflux => decreased systemic availability
- inhibitors (cyclosporin/verapamil) overcome BBB and enhance CNS accessibility

15

Describe the following features for OATs:
- type
- substrate
- tissue expression
- prototypical drugs
- inhibitors
- clinical significance/drug interactions

Type - influx, a-kg antiporter
Substrate - organic anions, broad range, low Mr
Tissue Expression - liver, kidney
Drugs - methotrexate (anti-cancer), NSAIDs, cidefovir (anti-viral)
Inhibitors - probenecid
Clinical Significance/Drug Interactions
- NSAIDs block OAT1-mediated methotrexate elimination => increased methotrexate toxicity
- probenecid prevents cidefovir renal uptake => blocks cidefovir-induced nephrotoxicity

16

Describe the following features for OATPs:
- type
- substrate
- tissue expression
- prototypical drugs
- inhibitors
- clinical significance/drug interactions

Type - influx, HCO3 (bicarb) exchanger
Substrate - amphipathic anions, high Mr
Tissue Expression - broad; gut, liver, kidney
Drugs - statins
Inhibitors - cyclosporins, macrolides
Clinical Significance/Drug Interactions
- OATP1B1 polymorphisms => decreased hepatic statin uptake => decreased clearance => increased toxicity
- cyclosporin blocks statin uptake => increased toxicity

17

Describe the following features for OCTs:
- type
- substrate
- tissue expression
- prototypical drugs
- inhibitors
- clinical significance/drug interactions

Type - influx, passive facilitated diffusion
Substrate - small cations
Tissue Expression - gut, kidney, liver, other
Drugs - cimetidine, cisplatin, metformin, procainamide
Inhibitors - cimetidine
Clinical Significance/Drug Interactions
- cimetidine blocks OCT renal uptake of many drugs => increased plasma concentration
- cimetidine blocks OCT renal uptake of cisplatin => prevents cisplatin induced nephrotoxicity

18

Describe the following features for MATEs:
- type
- substrate
- prototypical drugs
- inhibitors
- clinical significance/drug interactions

Type - non-ATP efflux, proton exchanger (secondary active)
Substrate - small cations
Drugs - cimetidine, cisplatin, metformin, procainamide
Inhibitors - cimetidine
Clinical Significance/Drug Interactions
- cimetidine blocks OCT renal uptake of many drugs => increased plasma concentration
- cimetidine blocks OCT renal uptake of cisplatin => prevents cisplatin induced nephrotoxicity
- main role of MATEs are to eliminate OCT-substrate drugs (renal secretion into urine, liver secretion into bile), excretion of (+) drugs,

19

Describe the following features for P-gps:
- type
- substrate
- prototypical drugs
- inhibitors
- clinical significance/drug interactions

Type - ATP efflux, active transporter
Substrate - broad specificity, bulky hydrophobic, neutral or (+) charge
Drugs - digoxin, loperamide, etoposide
Inhibitors - cyclosporin, verapamil
Clinical Significance/Drug Interactions
- cyclosporin inhibits p-gp mediated elimination of digoxin => increased systemic availability
- st. john's wart/rifampicin induce p-gp expression => increased efflux => decreased systemic availability
- inhibitors (cyclosporin/verapamil) overcome BBB and enhance CNS accessibility

20

Describe the following features for P-gps:
- type
- substrate
- prototypical drugs
- inhibitors
- clinical significance/drug interactions

Type - ATP efflux, active transporter
Substrate - broad specificity, bulky hydrophobic, neutral or (+) charge
Drugs - digoxin, loperamide, etoposide
Inhibitors - cyclosporin, verapamil
Clinical Significance/Drug Interactions
- cyclosporin inhibits p-gp mediated elimination of digoxin => increased systemic availability
- st. john's wart/rifampicin induce p-gp expression => increased efflux => decreased systemic availability
- inhibitors (cyclosporin/verapamil) overcome BBB and enhance CNS accessibility

21

Explain the relationship between OCTs and MATEs.

OCTs transport drugs from the blood into renal cells (influx)
MATEs transport drugs from the renal cells into the tubule lumen (urine) (efflux)

22

Explain the effects of SNPs on OCT/MATE activity.

- affects pharmacokinetics (PK) of many organic cationic drugs (metformin)
- metformin is very basic, acts in the liver, and is eliminated by renal secretion
- SNPs cause loss of OCT/MATE activity => decreased kidney uptake => decreased clearance => increased systemic availability

23

Describe the role of cisplatin on OCT/MATE activity.

- cisplatin is a chemotherapeutic primarily eliminated by the kidneys
- limited by nephrotoxicity
- when co-administered with cimetidine => cimetidine blocks OCT => prevents renal uptake => prevents nephrotoxicity and increases elimination

24

What is the main role of ABC transporters?

systemic drug clearance from gut, bile, urine luminal brush borders
- upregulated in cancer => drug resistance
- prevents xenobiotic access to BBB