SLC and ABC family carrier proteins

Two main transporter superfamilies

In pharmacology, membrane transport is viewed as a fundamental process determining a drug's fate in the body. Two key classes of proteins are distinguished:

• SLC superfamily (from Solute carrier). Their function is based on secondary active transport and facilitated diffusion (diffusio facilitata). A crucial characteristic of this family is bidirectionality. This means that the transport of substances can occur both into the cell and in the opposite direction.
• ABC superfamily (from ATP-binding cassette). These proteins carry out primary active transport, which directly utilizes the energy released during ATP hydrolysis. They are characterized by unidirectional movement: they selectively transport molecules predominantly out of the cell, functioning as pumps.

P-glycoprotein and protective efflux

A key mechanism protecting our cells from toxic xenobiotics is the efflux system, i.e., the expulsion of substances outward. It ensures the strictly ATP-dependent removal of molecules.

The primary role here is played by multidrug resistance proteins. The most common and studied representative is P-glycoprotein. This same group includes the MDR1 protein (from Multidrug resistance protein 1) and BCRP (breast cancer resistance protein).

Anatomically, P-glycoprotein is present in tissues responsible for barrier and excretory functions. It can be found on the membranes of intestinal enterocytes, hepatocytes, renal tubular epithelium, and endothelial cells of various blood-tissue barriers (including the blood-brain barrier).

The effect of transporters on pharmacokinetics

The main task of P-glycoprotein is the active "pumping out" of lipophilic compounds from the cytoplasm. This activity directly interferes with all major stages of drug pharmacokinetics:

1. Absorption. In the small intestine, the protein pumps drug substances out of the enterocyte back into the intestinal lumen. This reduces the overall completeness of drug absorption into the systemic circulation.
2. Distribution. At the level of blood-tissue barriers, the transporter removes molecules from the endothelial cytosol directly into the vascular lumen. This creates a powerful obstacle to drug penetration into tissues, thereby protecting vital organs (e.g., the brain).
3. Excretion. In liver and kidney cells, P-glycoprotein ensures the active secretion of lipophilic compounds into bile and urine. This leads to a significant acceleration of drug elimination from the body.

Resistance and drug interactions

Historically, these transporter proteins were first discovered in malignant tumor cells. Tumor cells are capable of significantly increasing the production (overexpressing) of P-glycoprotein. The protein begins actively pumping antineoplastic drugs (cytostatica) out of the cytoplasm, leading to the development of multidrug resistance and a sharp decrease in chemotherapy efficacy.

In addition to oncology, transporter activity is of paramount importance when drugs are prescribed concomitantly:

• P-glycoprotein inhibitors (quinidine — Chinidinum, lidocaine — Lidocainum, verapamil — Verapamilum) suppress its function. Normally, the protein pumps digoxin back into the intestinal lumen. If a patient takes quinidine, this process is inhibited: the concentration of digoxin in the blood rises dangerously, provoking the risk of cardiac glycoside intoxication. Furthermore, blockade of the transporter facilitates the transfer of toxic substances (cyclosporine, saquinavir) across the placenta to the fetus.
• P-glycoprotein inducers (morphine — Morphinum, dexamethasone — Dexamethasonum, St. John's wort preparations — Hypericum) enhance its activity. This leads to the accelerated elimination of substrates and a drop in their clinical efficacy. A classic example: St. John's wort extract reliably reduces the effectiveness of the antidepressant amitriptyline.

It is important to remember interindividual variability. The synthesis of these proteins is tightly regulated by genes subject to polymorphism and also exhibits pronounced sex differences, which together explain the differences in therapeutic response among different patients.

Briefly: answers to topical questions

Class and exam questions

What else to study on this topic

• Genetic polymorphism of genes encoding transporter proteins.
• Sex differences in the pharmacokinetics of substrate drugs.
• Protective function of endothelial cells in blood-tissue barriers.
• Mechanisms of transplacental transfer and fetal protection.

Other topics in "General Pharmacology"

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