Pharmacology of Drug Transporters Flashcards
By mediating update and efflux, what effect do drug trasnporters have on drug response?
plasma/drug concentration
drug distribution
drug efficacy
drug toxicity
Describe carrier-mediated drug transport.
What determines the rate of transport? What factors can affect this?
Cargo forms complex with transporter
Transport is subject to saturability
Transport can be reversible (depending on concentration gradient)
Transport is similar to enzyme kinetics
Rate of transport determined by Michaelis-Menten kinetics
Transport can be inhibited by other compounds
How are drugs transported across epithelial/endothelial barriers? (Give examples of what these barriers are)
Gut lumen/blood
Blood/bile
Blood/urine
Blood/CNS
Influx and Efflux transporters co-operate to promote
vectorial transport of drugs across epithelial/endothelial barriers
How is tissue-specific drug uptake established?
Selective expression of transporters promotes tissue-specific
drug uptake and barrier functions
Drug efficiently
taken up
into Tissue 1- drug response
Drug not a substrate
for influx transporter
expressed in Tissue 2
- No drug uptake
Efflux transporters form a
“drug-barrier” by exporting
any drug taken up
by influx transporters (BBB)
What is the pharmacokinetic role of drug transporters in intestinal epithelia?
absorption/excretion
What is the pharmacokinetic role of drug transporters in target tissues?
selective drug uptake/distribution
What is the pharmacokinetic role of drug transporters in liver epithelia?
hepatic uptake/metabolism/elimination
What is the pharmacokinetic role of drug transporters in kidney epithelia?
clearance/elimination
What is the pharmacokinetic role of drug transporters in CNS endothelium?
BBB
What are the eliminating organs?
kidney
liver
drugs can undergo excretion from liver or kidney
How will decreased update and/or decreased efflux in liver/kidney affect the following:
clearance
plasma concentration
target organ concentration
toxicity
decreased clearance
increased plasma concentration
increased target organ concentration
increased toxicity
How would increased uptake and/or decreased efflux in toxicological target organ (brain) affect the following:
cellular concentration
toxicity
increased cellular conc.
increased toxicity
If a drug inhibits transport of endogenous transporter substrates, how will plasma or cell concentrations be affected; how will toxicity be affected?
plasma OR cell concentrations will increase
(depending on situation Drug 2 could bind transporter and prevent transport of Drug 1 and thus there would be reduced efficacy of Drug 1 due to decreased uptake and also increased plasma conc. of Drug 1 leading to toxicity)
toxicity will increase
(drugs can compete for transport protein)
What are the two major classes of transporter proteins implicated in drug transport?
Solute Carrier Superfamily (SLC)
ATP Binding Cassette (ABC) super family
What type of transporter is the SLC?
ATP dependent?
predominantly influx/uptake transporters, (some efflux)
non ATP dependent
What type of transporter is the ABC transporter?
ATP dependent efflux transporter
What are the 4 most important subfamilies of SLC transporter superfamily?
OAT (organic anion transporters)
OATP (organic anion transporting polypeptides)
OCT (organic cation transporters)
Mate (multi-drug and toxin extrusion transporters) - this is exception and is efflux transporter
Most SLC are influx/uptake transporters; what is the exception?
MATE
Multi-drug and Toxin Extrusion transporters
Is MATE transporter SLC or ABC?
SLC
What are the 3 most important sub-families of ABC superfamily?
P-gp/MDR1
P-glycoprotein/Multidrug resistance 1
BCRP
Breast Cancer Resistance Protein
MRPs
Multidrug resistance proteins
What type of transporter is the OAT transporter? Describe/draw its mechanism?
Where is it expressed?
tertiary active transport
Slide 13
Expressed in the liver and kidney proximal tubules (and other tissues)
Describe the action of OAT transporters on the basolateral membrane and the apical membrane.
expressed in liver and kidney PT
uptake from blood across basolateral membrane to liver or kidney
renal reabsorption
What is the substrate specificity of OAT transporters? (List endogenous and drug substrates)
broad range of low Mr substracts
Endogenous: cGMP; Bile salts; Citric acid cycle intermediates; Hormones
Drugs: Methotrexate (anti-cancer); NSAIDs; cidefovir (anti-viral)
Describe what happens when Methotrexate and NSAIDs interact.
Methotrexate: - cancer/Rheumatoid Arthritis
- narrow therapeutic index
- eliminated via renal tubular elimination
- NSAIDs are inhibitors of OAT1 transporter activity
so methotrexate elimination decreases and plasma conc. increases
Describe the drug interaction between Probenecid and Cidefovir.
Probenecid is a potent inhibitor of OAT1
Cidefovir is an anti-viral used to treat CMV retinitis, transported into proximal tubules by OAT1 but treatment is limited by severe renal toxicity, so Cidefovir is always co-administered with Probenecid bc probenecid will block OAT1 dependent Cidefovir uptake into the PT; will still be cleared eventually but this time by glomerular filtration; not through transport across the renal epithelium
What kind of transporters are OATP transporters?
Where are they expressed?
uptake/influx transporters:
-electroneutral exchangers; transports substrates in exchange for HCO3-
Broadly expressed in many tissues including gut, liver and kidney proximal tubules
(intestinal uptake, renal reabsorption, hepatic reabsorption from bile, and uptake from blood into kidney or liver)
What is the substrate specificity of OATP transporters?
Broad range of substrates; Amphipathic Anions, Mr greater than 350 Da
Endogenous: Bile acids, steroids, thyroid hormones
Drugs: Statins, Antibiotics, Anti-cancer drugs, Anti-diabetes drugs
Inhibitors: Cyclosporin, Macrolide antibiotics, Flavanoids
Describe the role of the OATPB1 in response to statin drugs.
STATIN (anti-cholesterol)
OATPB1 is responsible for STATINs principle effects in liver (first pass effect)
OATB15 and OATB115 have decreased transporter activity (decreased STATIN uptake and decreased STATIN efficacy)
- increased systemic STATIN expsure and increased statin toxicity
- Cyclosporin is potent inhibitor of OATP1B1 and blocks STATIN uptake - decreased STATiN uptake and decreased efficacy, increased risk of toxicity
Statins left in blood stream not taken up by liver … BAD bc side effects are sever and can lead to death. Have access to muscle and cause toxicity…
cyclosporin blocks transporter
Statin in muscle causes myopathy and rhabdomyolysis
What is the mechanism by which OCT transport substrates?
uptake/influx transporters
- mediate simple passive facilitated diffusion of substrates
- (Na+/H+-independent)
Where are OCT transporters expressed?
gut, kidney, liver and other tissues
What type of substrate are OCT transporters specific for?
Substrate specificity: Small positively charged compounds
Endogenous: monoamine neurotransmitters, creatine, catecholamines
Drugs: Cisplatin (chemotherapy), metformin (diabetes); cimetidine (H2 receptor antagonist), procainamide (antiarrythmic)-narrow therapeutic window
Describe the mechanism of MATE transporters.
What kind of molecules do they transport? Substrate specificity? Where are they expressed?
What is their role/what are they responsible for?
transport organic cations
secondary active transport driven by H+ antiport
play a major role in excretion of positive charged drugs
overlapping substrate specificity with OCTs
primary responsible for secretion of OCT transported substates
expressed in liver and kidney luminal brush border surfaces
Responsible for:
- renal tubular secretion of cationic drugs into urine
- hepatic elimination of cationic drugs into bile
Describe the effects of multiple SNPs on OCT and MATE activity
influence the PK of multiple cation drugs (esp metformin)
Metformin is a very BASIC anti-diabetic drug that acts in the liver and is eliminated unchanged by renal tubular excretion
SNPs lead to loss of transporter activity, decreased kidney uptake/excretion and increased systemic drug availability
Describe the drug which causes most drug interactions mediated by OCT/MATE.
Most drug interactions mediated by OCT/MATE are caused by CIMETIDINE
an histamine H2 receptor antagonist used in the treatment acid peptic disorder
extensively eliminated via the kidney
prevents renal elimination of other OCT-dependent drugs
so when prescribed alongside Procainamide; cimetidine blocks its excretion and so plasma conc. of procainamide goes up
Describe how Cisplastin induced nephrotoxicity can be prevented.
Cisplatin is a chemotherapeutic agent used in the treatment of certain cancers
- primarily eliminated via renal tubular excretion
- use is limited by nephrotoxicity
- Co-administration of CIMETIDINE blocks Cisplatin uptake into the kidney and prevents Cisplatin-induced nephrotoxicity
What is the effect of cimetidine on transporters.
an histamine H2 receptor antagonist used to treat acid peptic disorders
eliminated by kidney
prevents renal elimination of other OCT dependent drugs
(like procainamide)
but co-administered w Cisplatin so that its uptake into kdiney is blocked and Cisplatin-induced nephrotoxicity is prevented
Cisplatin and Cidefovir are both drugs that cause nephrotoxicity when taken up by their respective transporters. What transporters take them up; and what drugs can be prescribed with them to prevent a toxic effect?
Cidefovir- transported by OAT1; must be prescribed with Probenecid
Cisplatin is transported by OCT; must be prescribed with cimetidine (blocks OCT transporters in kidney)
By what mechanism do ABC transporters transport drugs?
Use hydrolysis of ATP to generate the energy needed to move substrates across membranes against their concentration gradient
Where are ABC transporters found?
Present on the apical luminal brush border membranes of gut, liver and kidney epithelia, endothelial cells of BBB
Involved in the active secretion of drugs across epithelial surfaces into the gut lumen, urine and bile
Describe the substrate specificity for P-gp/MDR1.
What drugs/inhibitors/inducers?
ABC transporter
broad substrate specificity
-typically bulky hydrophobic structures with neutral/positive charge
specificity overlaps with CYP3A4
Digoxin and Loperamide
Cyclosporin inhibits
Ripampin and St John’s wort induce expression of P-gp
What transporter extrudes glutathione, glucuronide and sulfate conjugates?
Multidrug resistant proteins (MRPs)
an ABC transporter
(substrates are ampipathic molecules with at least one negative charge)
What is the role of the BBB?
Main function is to protect the brain from xenobiotics and toxins
Discuss the formation of the BBB. How/why is it effective?
tight junctions prevent ions and large molecules passing between endothelial cells
P-gp/MRP/BCRP ABC family efflux pumps form a barrier to a large range of drugs an dother compounds by actively transporting these compounds back into the blood and thereby preventing their entry into the CNS (OATP transporters to get in)
-BBB extrudes most drugs other than those small (less than 400Da) and lipophilic- only about 1% of drugs gain access and are active in CNS.
A patient presents with respiratory depression in the ER. You check their medications and realize they have been taking Loperamide as well as cyclosporin. Explain the mechanism of what has happened.
Loperamide is anti-diarrheal opioid receptor agonist that is a potent substrate for P-gp so does NOT cross BBB
cyclosporin inhibits P-gp so Loperamide can cross BBB and cause respiratory depression
Would a tumor cell want to increase or decrease expression of P-gp/MDR1 in their tumor cells? Explain.
upregulates expression of P-gp/MDR1
(associated with a more aggressive phenotype, poorer prognosis and decreased sensitivity to chemotherapeutic drugs
-increased expression of P-gp MDR1 in tumor cells promotes efflux of anti-cancer drugs
An ampipathic drug enters its target tissue but in the presence of cyclosporin its plasma concentration increases to potentially toxic levels.
What drug?
Where does it enter/what organ and membrane?
Through what transporter?
statins, OATP B1 transporter on the basolateral liver membrane
When administered alongside Rifampicin, a certain drug’s bioavailability decreases.
What transporter? Where? What membrane?
Rifampin is an inducer of P-gp which is an efflux transporter present in gut, kidney liver apical membrane
