Transporters Flashcards
What is access in terms of the mechanisms of drug variability?
Access is how the drug: gets to the brain, gets to the correct part of the brain, and having the concentration-dependent effects
What is genome variability in terms of the mechanisms of drug variability?
Polymorphisms that lead to alterations in drug metabolism, drug targets, or drug transporters. Some people express it (transporters) more, naturally
What is “disease-related mechanisms” in terms of the mechanisms of drug variability?
Disease progression despite treatment, structural brain alterations and/or network changes, alterations in drug target(s). or alterations in drug uptake into the brain
What is “drug-related mechanisms” in terms of the mechanisms of drug variability?
(Drug) tolerance, induction of drug-metabolizing enzymes or drug transporters, and ineffective mechanisms of drug action (change in receptor number, density)
Define tolerance
Increasing the dosage of the drug in order to get the same effect. It is not the same as addiction
What maintains the Blood-Brain Barrier (BBB)?
The capillary network supplying blood to the brain
True or False: The capillary endothelial cells in the brain are the same as those found in the peripheral tissues
False: The BBB is special and different in many ways
How do tight junctions provide an effective barrier against the paracellular movement of the molecules?
The tight junctions have high electrical resistance since they are spaces with electrical charge, giving high levels of resistance
Where is there good transcellular movement?
Peripheral endothelial cells
True or False: There is no good transcellular movement of molecules in brain endothelial cells
True: Because of gap junctions
What do astrocytes do?
The ends of the astrocytes contact with the brain capillaries, which essentially separate the capillaries from the neurons
The BBB is both _________ and a delicately _________
physical ; balanced set of transport mechanisms
What type of molecules is able to penetrate through the barrier relatively easily?
Lipid-soluble molecules
Why are lipid-soluble molecules able to penetrate through the barrier more easily?
They are able to use the lipid membranes of the cells, as compared to water-soluble molecules (i.e.: ions) that need specialized carrier-mediated mechanisms
Which type of molecules are drugs (for addiction) usually are made of?
Lipid-soluble molecules, because they can easily penetrate through the barrier relatively easily. They are usually very small but the production of these drugs can alter the size
What are the five main points on why the BBB peripheral capillaries are different?
- compounds DIFFUSE across the endothelium
- compounds can use the PARACELLULAR PATHWAY (intercellular pore)
- compounds can use FENESTRATIONS
- compounds can use VESICLES
- compounds can use FACILITATED DIFFUSION and ACTIVE TRANSPORTERS (influx and efflux)
What happens to the cells during fenestrations?
The cell dies, which creates a gap. While the replacement is getting built, there is more opportunity for drugs* to get to the epithelia
What type of compounds can diffuse through the brain capillaries?
Fat-soluble compounds
True or False: There are gap junctions between the endothelia
False: The junctions between endothelia are tight, and no paracellular pathway and fenestrations occur unless diseased
True or False: There is very little vesicular transport in the brain capillaries
True: There are lots of vesicular transports in the brain itself (used for communication between neurons) but once they hit the BBB, it stops
What do transporters in the BBB do?
They take stuff out from the brain and shift them back to the blood
What are pericytes?
They help regulate vascular tone and blood flow. They also assist with immune function by removing cellular debris and act as another layer to keep the BBB impermeable
Pericytes are _________ cells that sit adjacent to _________ cells
contractile ; endothelial
What can cause the breakdown of BBB? Why is it important to avoid this from happening?
Deficiencies in pericytes can result in the breakdown of BBB. The breakdown of BBB can be fatal since the brain is so complex (hard to treat)
What are astrocytes?
They form the astroglial/astrocytic sheath in the brain and the spinal cord. Astrocytes have support roles for both neurons and endothelial cells by exchanging ions and nutrients
What are the general properties of drugs that easily cross the BBB?
Small, fat-soluble, non-ionized. This is with the exception of Lithium (ionized) and cocaine (water-soluble)
What is an example of the protective mechanism for the BBB?
BBB expresses efflux transporters on the Apical membrane, that reflux (efflux) substrates back into the blood
What are the two most important efflux transporters on the apical membrane?
MDR1 (a.k.a. P-gp or P-glycoprotein) and BCRP (Breast Cancer Resistance Protein)
Between MDR1 (a.k.a. P-gp) and BCRP, which has the widest effects on drug transport?
P-glycoprotein
In what family do MDR1 (a.k.a. P-gp) and BCRP belong to?
ABC family of transport proteins
What two transporters on the apical membrane are expressed in humans?
OATP 2B1 and OATP1A2
In what family do OATP 2B1 AND OATP 1A2 belong?
Organic Anion Transport Protein family
What is LAT1?
It is the human L-type amino acid transporter that exists on both the apical and basolateral membrane. It is primarily used for importing biochemicals required for cellular (and brain) health
What is OCTN2?
It is the Organic Cation transporter (Type 2) that is found on the basolateral membrane alone
Why is LAT1 (human L-type amino acid transporter) a potential drug target?
Because amino acids are big and charged
What can happen to people with higher expression of P-gp (MDR1) if they get administered with anti-epileptic drugs?
Higher expression of P-gp causes resistance to anti-epileptic drugs, which means that the drug is prevented from entering the brain. The drugs will have no effects because the drug isn’t getting in
What needs to be done to patients who express higher levels of P-gp and need anti-epileptic drugs?
Take higher doses of drugs (as compared to others who have the same severity of the disease)
What can happen to people with higher P-gp (MDR1) and BCRP if they get administered with anti-HIV drugs?
They are resistant to the HIV viral load suppression and have higher levels of neuro-AIDS (HIV in the brain)
What anti-HIV drugs are affected by P-gp (MDR1)?
RAINS: ritonavir, amprenavir, indinavir, nelfinavir, saquinavir
What anti-HIV drug is affected by BCRP?
lamivudine
Why are brain tumors one of the most lethal cancers?
Because they respond poorly to current therapies and because most malignant brain tumors recur
What do “solid” type tumors do?
Upregulate transporters like P-gp and BCRP
Why is the upregulation of transporters lethal?
When the tumors themselves upregulate the transporters, the anti-cancer drug gets pumped out of the tumor before it can even kill the cancer cells. This will cause the cancer cells to continue to divide in the brain
What are the anti-cancer drugs affected by P-gp?
(DOXOrubicin, DAUNOrubicin, EPIrubicin, IDArubicin), (ETOposide, TENIposide), (VINBLAStine, VINCRIStine), docetaxel, methotrexate, mitoxantrone, paclitaxel
What are the anti-cancer drugs affected by BCRP?
anthracyclines (e.g.: doxorubicin), bisanthene, irinotecan, methotrexate, mitoxantrone, topotecan
The expression of MPR1, 2, 3, 4, 5 affects drugs for _______
anti-cancer drugs for both P-gp (MDR1) and BCRP
What causes some of the variability of antipsychotics and antidepressants?
Due to the transporter expression at the BBB and less entry into the brain (transporters pump the drugs out of the brain)
