Drug Transporters Flashcards
What are some examples of Neurotransmitters that use Transport Proteins?
Adrenaline
Noradrenaline – noradrenaline reuptake transporter
Dopamine – dopamine reuptake transporter
Serotonin 5-hydroxytryptamine (5-HT) - serotonin reuptake transporter
What is Passive Transport?
Movement of molecules down concentration gradient.
Simple diffusion – movement of small or lipophilic molecules across membrane
Facilitated diffusion – movement of large or charged molecules via membrane proteins (transporter (with binding site for molecule) or channel).
What are Drug Transporters?
Hydrophilic drugs are transported across the plasma membrane via transmembrane proteins (transporters/carriers).
Most drugs cross plasma membranes by passive diffusion or transporter .
What is Active Transport?
Movement of molecules against concentration gradient.
Primary active transport – involved direct use of metabolic energy (e.g. ATP hydrolysis) to mediate transport. Via pumps
Secondary active transport – involves coupling the molecule with another moving along an electrochemical gradient. Via carriers.
Requires specific binding of two substances for transport to occur. If these transported substances move in the same direction this is called symport transport, if they move in opposite directions it is called antiport
What are some Factors affecting Transport Activity?
Facilitated diffusion and active transport show saturation kinetics as they both involve specific binding. Transport depends upon the number of transport proteins in the membrane (at high concentrations there comes a point where all transporters in the membrane is bound and therefore rate cannot increase) and the rate of transport (as concentration of transported substance increases the rate of transport increases)
What are ATP-binding cassette (ABC) transporters?
Influx/uptake transporters uptake a large variety of nutrients, biosynthetic precursors, trace metals and vitamins.
Efflux/export transporters transport lipids, sterols and drugs out of cells.
Made up of two nucleotide-binding domains with ATPase activity and two transmembrane domains. In humans ABC transporters exist as either full transporters with all domains on the same polypeptide chain, or complexes of two half transporters
Associated with drug resistance such as antibiotic and anti-cancer agents
Multidrug resistant transporters (MDRs) are a specific type of ABC transporter commonly overexpressed in cancer cells
What are Solute Carrier (SLC) transporters?
Either facilitative transporters or secondary active transporters. Facilitate movement of ions, nutrients and drugs into cell
What are Organic Anion Transporting Polypeptides (OATP)?
Transport several structurally diverse amphipathic substances including steroid hormones, bile acids, statins, antihypertensives, antibiotics, antifungals and chemotherapeutic agents.
Important roles in kinetics of drug disposition and in drug-drug interactions when two or more xenobiotics that are a substrate for the same OATP are given concurrently.
Several drugs, herbs and foods can inhibit OATP and thus effect drug uptake
What is the role Drug Transporters have in ADME?
Role in drug absorption – transporters affect drug uptake into the intestine, influences bioavailability of drug
Role in drug distribution – dependent on transporter distribution in blood-brain barrier, liver and kidneys. This impacts distribution of drugs to various tissues
Role in drug elimination – transporters in renal and hepatic excretion are affected impacting clearance of drugs from the body
Describe the effect of monoamine reuptake inhibitors ???
Monoamine reuptake inhibitors competitively inhibit binding of the monoamine to the substrate-binding compartment at the transporter, blocking the neurotransmitters
- NSRIs block NET and SERT
- SNRIs selectively block NET
- SSRIs selectively block SERT (SERT vs NET inhibition ration > 100)
- NDRIs block NET and DAT
What is Methotrexate?
An antimetabolite used in cancer therapy, has a similar structure to folic acid. Inhibits a key enzyme in DNA synthesis Dihydrofolate reductase
What is Levodopa?
A prodrug for the neurotransmitter dopamine, used in treatment of Parkinson’s disease. Dopamine cannot cross the BBB. Levodopa is similar in structure to an amino acid so used amino acid transporter proteins to be carried across the cell membrane, once in the brain a decarboxylase enzyme removes the acid group and generates dopamine
