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Drug Transporters Flashcards

1
Q

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

A
  • balance influx and efflux
  • determine plasma drug concentration by mediating distribution, efficacy, and toxicity
  • affected by tissue expression, activity, polymorphisms, and inhibitors
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2
Q

Describe carrier-mediated drug transport.

A
  • 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
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3
Q

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

A

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

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4
Q

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

A

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

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5
Q

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

A

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)
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6
Q

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

A
  • 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
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7
Q

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

A
  • role: statin uptake into liver cells
  • polymorphisms OATP1B15 and OATP1B115 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
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8
Q

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

A

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

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9
Q

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

A

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

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10
Q

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.

A 
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

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11
Q

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

A
  • upregulate P-gp/MDR1

- associated with poor

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12
Q

Describe the following features for OCTs:

  • type
  • substrate
  • prototypical drugs
  • inhibitors
  • clinical significance/drug interactions
A

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

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13
Q

Describe the following features for MATEs:

  • type
  • substrate
  • prototypical drugs
  • inhibitors
  • clinical significance/drug interactions
A

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

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14
Q

Describe the following features for P-gps:

  • type
  • substrate
  • prototypical drugs
  • inhibitors
  • clinical significance/drug interactions
A

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

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15
Q

Describe the following features for OATs:

  • type
  • substrate
  • tissue expression
  • prototypical drugs
  • inhibitors
  • clinical significance/drug interactions
A

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

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16
Q

Describe the following features for OATPs:

  • type
  • substrate
  • tissue expression
  • prototypical drugs
  • inhibitors
  • clinical significance/drug interactions
A

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
Q

Describe the following features for OCTs:

  • type
  • substrate
  • tissue expression
  • prototypical drugs
  • inhibitors
  • clinical significance/drug interactions
A

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
Q

Describe the following features for MATEs:

  • type
  • substrate
  • prototypical drugs
  • inhibitors
  • clinical significance/drug interactions
A

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
Q

Describe the following features for P-gps:

  • type
  • substrate
  • prototypical drugs
  • inhibitors
  • clinical significance/drug interactions
A

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
Q

Describe the following features for P-gps:

  • type
  • substrate
  • prototypical drugs
  • inhibitors
  • clinical significance/drug interactions
A

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
Q

Explain the relationship between OCTs and MATEs.

A

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

22
Q

Explain the effects of SNPs on OCT/MATE activity.

A
  • 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
Q

Describe the role of cisplatin on OCT/MATE activity.

A
  • 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
Q

What is the main role of ABC transporters?

A

systemic drug clearance from gut, bile, urine luminal brush borders

  • upregulated in cancer => drug resistance
  • prevents xenobiotic access to BBB

Pharmacology (22 decks)

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