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PT 1 > L6 The Pharmacology of Drug Transporters > Flashcards

L6 The Pharmacology of Drug Transporters Flashcards

1
Q

The balance between ___ and ___ via transporters affects the plasma and tissue drug concentration.

A

Influx; efflux

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2
Q

What is the normal endogenous function of influx/uptake transporters?

A

To take up nutrients, essential metabolites, and signaling molecules in order to maintain normal cell function and metabolism

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3
Q

What is the normal endogenous function of efflux transporters?

A

Excretion and detoxification via the bile/urine/gut

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4
Q

___ expression of transporters promotes tissue-specific drug uptake and barrier functions.

A

Selective

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5
Q

Where are drug transporters found (5 locations) and how do these affect pharmacokinetics?

A
  1. Intestinal epithelial (absorption/excretion)
  2. Target tissues (selective drug uptake/distribution)
  3. Liver epithelial (hepatic uptake/metabolism/elimination)
  4. Kidney epithelia (clearance/elimination)
  5. CNS endothelium (blood brain barrier)
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6
Q

What happens when uptake and/or efflux of a drug is decreased in the liver and kidney?

A

Decreased clearance, increased plasma concentration, increased target organ concentration, increased chance of toxicity

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7
Q

What happens when uptake increases and/or efflux decreases in the target organ?

A

Increased cellular concentration, increased chance of toxicity

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8
Q

What happens when a drug inhibits transport of endogenous transporter substrates?

A

Increased plasma or cellular concentration of substrates, increased chance of toxicity

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9
Q

What are the two major classes of transporter proteins implicated in drug transport?

A
  1. SLC - solute carrier superfamily

2. ABC - ATP-binding cassette superfamily

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10
Q

What is the primary function of SLCs?

A

Influx/uptake (except MATE –> non-ATP-dependent efflux)

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11
Q

What are the 4 most important sub-families of the SLC superfamily?

A
  1. OAT (Organic Anion Transporters)
  2. OATP (Organic Anion Transporting Polypeptides)
  3. OCT (Organic Cation Transporters)
  4. MATE (Multi-drug and Toxin Extrusion Transporters)
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12
Q

What is the primary function of ABCs?

A

ATP-dependent efflux

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13
Q

What are the 3 most important sub-families of the ABC superfamily?

A
  1. P-gp/MDR1 (P-glycoprotein/Multidrug resistance 1)
  2. BCRP (Breast Cancer Resistance Protein)
  3. MRP (Multi-drug Resistance Proteins)
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14
Q

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

A

Probenecid is a potent inhibitor of OAT1. Cidefovir, an anti-viral used to treat CMV retinitis, is normally transported into the proximal tubules by OAT1, which leads to severe renal toxicity. Cidefovir is co-administered with probenecid to prevent this toxicity.

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15
Q

Describe the role of the OATP1B1 transporter in influencing the pharmacokinetics of the STATIN class of drugs

A

Normally, OATP1B1 transporters take up STATINs into the liver. Multiple SNPs in the transporter decrease activity, leading to decreased STATIN uptake/efficacy and increased systemic exposure/toxicity. In addition, cylosporin is an inhibitor of OATP1B1 and blocks STATIN uptake.

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16
Q

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

A

Most drug interactions mediated by OCT/MATE are caused by cimetidine, a histamine H2 receptor antagonist used to treat acid peptic disorder. It is a potent competitive inhibitor of OCT, preventing renal elimination of drugs dependent on OCT and leading to increased plasma concentrations of these drugs. It can also block Cisplatin uptake into the kidney and prevent nephrotoxicity.

17
Q

Where are ABCs located?

A

The apical luminal brush border membranes of gut, liver, and kidney epithelia (secrete drugs into gut lumen, urine, and bile) and the endothelial cells of the BBB

18
Q

ABCs are upregulated in certain ___ cells - what are the implications of this?

A

Cancer; implicated in resistance of cancer cells to chemotherapeutic drugs

19
Q

Describe the role of the ATP-binding class of transporters in contributing towards the integrity of the Blood Brain Barrier.

A

ABC family efflux pumps form a barrier to a large range of drugs and other compounds by actively transporting them back into the blood and preventing their entry into the CNS (excludes most drugs except those that are small and lipophilic)

20
Q

Describe the effects of cyclosporin on the pharmacokinetics of drugs that are substrates for the P-glycoprotein/MDR1 drug transporter and discuss the underlying mechanisms.

A

Cyclosporin inhibits P-gp/MDR1, leading to decreased drug elimination of substrates such as digoxin; this leads to increased systemic drug bioavailability and increased risk of drug toxicity

21
Q

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

A

Rifampicin and St. John’s wort induce increased expression of P-gp; this leads to increased drug efflux in gut/kidney/liver, decreased plasma concentration, and decreased drug efficacy

22
Q

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

A

Tumor cells often upregulate expression of P-gp/MDR1. This is associated with more aggressive phenotypes, poorer prognosis, and decreased sensitivity to chemotherapeutic drugs (efflux of anti-cancer drugs).

23
Q

Generally, SLC transporters are found where?

A
  1. Liver
  2. Kidney proximal tubules
  3. Gut (not OAT)/brush borders
24
Q

Describe transport via OAT.

A

Influx of organic anions (broad range of low Mr substrates) w/efflux of alpha-ketoglutarate, whose gradient is maintained by a Na/alpha KG co-transporter and Na/K ATPase

25
Q

Describe the effects of NSAIDs on methotrexate.

A

Methotrexate is a cancer/RA drug and it is eliminated via OAT in renal tubules. NSAIDs inhibit OAT1 activity, leading to decreased methotrexate elimination and increased plasma concentrations (toxicity).

26
Q

Describe transport via OATP.

A

Influx of organic anions (amphipathic and Mr > 350 Da) in exchange for HCO3-

27
Q

Describe transport via OCT.

A

Influx of small cations via passive facilitated diffusion

28
Q

Describe transport via MATE.

A

Effluxes organic cations via an H+ antiport

29
Q

Which two transporters have overlapping specificity and oppose each other?

A

OCT and MATE

30
Q

What are the typical substrates transported via ABCs?

A

Bulky hydrophobic structures with neutral or positive charges

31
Q

What are the typical substrates transported via BCRPs?

A

Neutral/negatively charged compounds

32
Q

What are the typical substrates transported via MRPs?

A

Amphipathic molecules with at least one negative charge

PT 1 (34 decks)

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