24. Drug Action on transporters Flashcards
Describe what solute carrier (SLC) transporters are.
- includes most transporters other than ABC proteins and ion channels
- do not require ATP
- facilitative or secondary active transporters
- uptake or efflux
List the different substrates of SLC transporters.
- inorganic ions
- nucleotides
- amino acids
- neurotransmitters
- sugars
- purines
- fatty acids
- drugs
How do mutations in SLC genes relate to human disease?
Mutations in SLC genes result in human disease
* ex. mutated SLC5A2 –> familial renal glucosuria
Explain the relation between SLC transporters and drug targets.
glucose transporters - targets diabetes
neurotransmitter transporters - antidepressant drugs
bile acid transporters - targets bild acid related diseases
salt transporters - diuretic drugs
uric acid reabsorption transporters - targets gout
peptide transporters - better drug delivery
Explain the mechanism of SLC5 transporters as targets for diabetes drugs.
SLC5A1 - encodes Na+/glucose cotransporter 1 (SGLT1), which has a major role in glucose absorption in the small intestine.
SLC5A2 - encodes Na+/glucose sotransporter 2 (SGLT2), which plays major role in renal glucose reabsorption.
Name examples of SLC5 transporters as targets for diabetes drugs. What do they do?
Canaglifozin, dapagliflozin, and empagliflozin are FDA-approved second-line therapeutic agents for patients whose diabetes is inadequately controlled by a single antidiabetic agent.
* SGLT2 inhibitors
* reduce plasma glucose levels and increasing urinary glucose excretion.
Explain SLC6 transporters.
SLC6 transporters are used as targets for antidepressants.
* SLC6A2 and SLC6A4
Explain SLC6A2.
SLC6A2 encodes norepinephrine transporter (NET), which is the reuptake transporter of norepinephrine in the synaptic space into presynaptic neurons.
* ex. duloxetine, venlafaxine, desvenlafaxine
Explain SLC6A4.
SLC6A4 encodes serotonin transporter (SERT), which is the reuptake transporter of serotonin in the synaptic space into presynaptic neurons.
* SSRIs: fluoxetine, paroxetine, sertraline, citalopram
Describe how SSRIs and SNRIs work as antidepressants.
- SSRIs and SNRIs reduce the clearance of serotonin and norepinephrine from the synapse.
- SSRIs and SNRIs increase activation of the neurotransmitters on ligand-gated ion channels and GPCR signaling
- SSRIs and SNRIs are widely used antidepressant drugs.
How are SLC10 transporters used as targets for bile acid related diseases?
Bile acids are required for digesti8on and absorption of fats and fat-soluble vitamins in the small intestine.
* over accumulation of bile acids = human disease
* SLC10A2 - encodes apical Na-dependent bile acid transporter (ASBT) –> plays key role in the enterohepatic circulation of bile acids
ASBT is closely related to what?
SLC10 transporters encode for ASBT
* ASBT is closely related to the occurence and treatment of diseases (hepatobiliary, inflammatory bowel, and metabolic diseases)
Explain the mechanism of SLC12 transporters as targets for diuretic drugs.
- SLC12A1 encodes Na+-K+-Cl- cotransporter (NKCC2), which is the major salt transporter in the kidney
- NKCC2 maintains urinary concentration and blood pressure
Explain the mechanism of diuretic drugs on SLC12 transporters.
Bumetanide and furosimide are loop diuretics –> inhibit NKCC2
* treat edematous states caused by heart failure, liver disease, and kidney disease
* treat hypertension
Explain the relation between gout drugs and SLC22 transporters.
- Gout is caused by the accumulation of monosodium urate monohydrate crystals in the joints and soft tissue –> result of hyperuricemia.
- SLC22A12 - encodes urate transporter 1 (URAT1)
- URATE1 is the primary uric acid reabsorption transporters expressed in the kidney.
Explain the mechanism of gout drugs on SLC22 transporters: Lesinurad.
Lesinurad (Zurampic) - FDA approved drug to treat high blood uric acid levels associated with gout.
* URAT1 transporter inhibitor
* discontinued in the US by its manufacturer for business reasons
Explain the mechanism of gout drugs on SLC22 transporters: Verinurad.
- URAT1 inhibitor that is used for gout, heart failure, and hyperuricemia
- designed to reduce uric acid levels in the bloodstream
Explain the role of SLC15 transporters.
- SLC15A1 encodes PepT1
- SLC15A2 encodes PepT2
- PepT1 and PepT2 are major route of dietary di-/tri-peptide absorption in the small intestine and kidneys
Explain the mechanism of SLC15 transport for drug delivery.
- Drug delivery technology has target4ed PepT1 and PepT2 to improve the pharmacokinetic properties of several drug molecules.
- The attachment of amino acids or small molecules/peptides to drug molecules –> creates prodrug.
- Prodrug is recognized by PepT1 and PepT2 –> transported into the body following oral administration
Explain ADME: pharmacokinetics
Absorption: move charged drugs from digestive tract into blood.
Distribution: move charged drugs into various tissues.
Metabolism: make drugs better transporter substrates.
Excretion: eliminate drugs via kidneys and intestines.
Describe the relation between drug transporter expression and plasma/organ drug concentrations.
- Decrease in transporter expression in a clearance organ –> lead to increased drug concentrations in plasma and target organs.
- Increase in transporter expression in a clearance organ –> decreased drug concentrations in plasma and target organs = drug can’t reach an effective level.
Describe the relation between uptake/efflux and exposure.
In target organs,** increased uptake or decreased efflux** can result in increased exposure to drug.
Describe the relation between competitive drugs and endogenous compound concentration.
When drugs compete with endogenous substrates, drugs can cause accumulation of the endogenous substance (which can be toxic after increased accumulation in the plasma/target organ)
Explain how drug transporters act as mediators for drug-drug interactions.
- If drug #1 is specifically take up into the tissue by a specific drug transporter and drug #2 is a substrate/inhibitor of the same drug transporter.
- Drug #2 binds competitively to the transporter and prevents transport of drug #1 –> reduced efficacy of drug #1 due to decreased uptake.
- Result: increased plasma concentration of drug #1 –> TOXICITY
