Transporters

membrane proteins that control the influx of essential nutrients and ions and the efflux of cellular waste, environmental toxins, and other xenobiotics. Two major superfamilies dominate the area of drug transporters: ATP-binding cassette (ABC) and solute carrier (SLC) transporters.

 Most ABC proteins are primary active transporters, which rely on adenosine triphosphate (ATP) hydrolysis to actively pump their substrates across membranes. Example: P-glycoprotein The SLC superfamily includes facilitated transporters and ion-coupled secondary active transporters. Example: serotonin transporter (SERT)

MEMBRANE TRANSPORTERS IN THERAPEUTIC DRUG RESPONSES

PHARMACOKINETICS: Important transporters located in intestinal, renal, and hepatic epithelia function in concert with metabolism of drugs in the selective absorption and elimination of endogenous substances and drugs Example: Folate/thiamine transporter drug substrate- Methotrexate Linked disease- Thiamine-responsive megaloblastic anemia

 PHARMACODYNAMICS: TRANSPORTERS AS DRUG TARGETS Membrane transporters are the targets of many drugs. For example, neurotransmitter transporters are the targets for drugs used in the treatment of neuropsychiatric disorders. SERT (SLC6A4) is a target for the selective serotonin reuptake inhibitors (SSRIs), a major class of antidepressant drugs.

 DRUG RESISTANCE Membrane transporters play critical roles in the development of resistance to anticancer drugs, antiviral agents, and anticonvulsants. P-glycoprotein, which exports many chemotherapeutics from cells, is overexpressed in tumor cells after exposure to cytotoxic anticancer agents. Other transporters (e.g., breast cancer resistance protein [BCRP], organic anion transporters, and several nucleoside transporters) also have been implicated in resistance to anticancer drugs.

Membrane Transporter Proteins: Classification

Membrane Transport Proteins

Selective Channels

Specific Carriers

Primary Active Transport

Facilitated Diffusion

Secondary Active Transport

ATP-powered pumps

Uniporters

Symporters

Antiporters

ATPases: P-type, F-type and ABC-type ATPases (ABC transporters)

Glut1-5

Pept1

NHE

ACTIVE TRANSPORT
Active transport requires energy input and transports solutes against their electrochemical gradients, leading to the concentration of solutes on one side of the plasma membrane and the creation of potential energy in the electrochemical gradient formed. Active transport plays an important role in the uptake and efflux of drugs and other solutes. Depending on the driving force, active transport can be subdivided into primary and secondary active transport

Primary Active Transport

Membrane transport that directly couples with ATP hydrolysis is called primary active transport. ABC transporters are examples of primary active transporters. They contain one or two highly conserved ATP binding cassettes that exhibit ATPase activity. ABC transporters mediate the unidirectional efflux of many solutes across biological membranes.

1. Ion transporters: Classic example: ATP driven ion pump Proton Pump. a. Organic anion transporter: aids absorption of pravastatin and atorvastatin. b. Organic cation transporter: aids in absorption of diphenhydramine.

2. ABC transporter: responsible for transporting small foreign molecules out of cells. Example: P-glycoprotein Responsible for effluxing hydrophobic anticancer drugs out of cells.

Secondary Active Transport

In secondary active transport, the transport across the plasma membrane of one solute S1 against its concentration gradient is driven energetically by the transport of another solute S2 in accordance with its concentration gradient. The driving force for this type of transport therefore is stored in the electrochemical potential created by the concentrationdifference of S2 across the plasma membrane. Depending on the transport direction of the solute, secondary active transporters are classified as either symporters or antiporters. Symporters, also termed co-transporters, transport S2 and S1 in the same direction, whereas antiporters, also termed exchangers, move their substrates in opposite directions

Co-transporter

Other example of co-transporter: H+oligopeptide cotransporter drug substrate: Valacyclovir

Antiporter

SLC9 Na+/H+ exchanger Drug substrate: Thiazide diuretics

Uniporter
Mechanism of transport