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 (Solute carrier transporters). Their function is based on secondary active transport and facilitated diffusion (diffusio facilitata). A crucial characteristic of this family is bidirectionality, meaning that substances can be transported either into the cell or in the reverse direction.
- ABC Superfamily (ATP-binding cassette transporters). These proteins perform primary active transport, directly utilizing energy released from ATP hydrolysis. They are characterized by unidirectional movement: they selectively transport molecules predominantly out of the cell, acting as molecular pumps.
P-Glycoprotein and Protective Efflux
A key mechanism protecting our cells from toxic xenobiotics is the efflux system, which pumps substances outward. This process relies on strictly ATP-dependent molecular removal.
The primary role is played by multidrug resistance proteins. The most widespread and studied representative is P-glycoprotein. This same group includes the MDR1 protein (Multidrug resistance protein 1) and breast cancer resistance proteins (BCRP/MDRP2).
Anatomically, P-glycoprotein is expressed 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).
Impact of Transporters on Pharmacokinetics
The primary task of P-glycoprotein is the active extrusion of lipophilic compounds from the cytoplasm. This activity directly interferes with all major pharmacokinetic phases of drug action:
- Absorption. In the small intestine, the protein pumps drug molecules out of the enterocyte back into the intestinal lumen, reducing overall systemic absorption.
- Distribution. At blood-tissue barriers, the transporter removes molecules from the endothelial cytosol directly into the vascular lumen, creating a powerful obstacle to drug penetration into tissues and thereby protecting vital organs (e.g., the brain).
- Elimination. In liver and kidney cells, P-glycoprotein facilitates the active secretion of lipophilic compounds into bile and urine, significantly accelerating drug elimination from the body.
Resistance and Drug Interactions
Historically, these transport proteins were first discovered in malignant tumor cells. Tumor cells can dramatically upregulate (overexpress) P-glycoprotein. The protein then actively pumps anticancer drugs (cytostatics) out of the cytoplasm, leading to multidrug resistance and a sharp decrease in chemotherapy efficacy.
Beyond oncology, transporter activity is critical when drugs are co-administered:
- P-glycoprotein inhibitors (Chinidinum, Lidocainum, Verapamilum) suppress its function. Normally, the protein pumps digoxin back into the intestinal lumen. If a patient takes quinidine, this process is inhibited: the blood concentration of digoxin rises dangerously, provoking the risk of digitalis toxicity. Furthermore, blockade of the transporter facilitates the transfer of toxic agents (e.g., cyclosporine, saquinavir) across the placenta to the fetus.
- P-glycoprotein inducers (Morphinum, Dexamethasonum, Hypericum extracts) enhance its activity, leading to accelerated elimination of substrates and a drop in their clinical efficacy. A classic example is St. John's wort extract, which reliably decreases the efficacy of the antidepressant amitriptyline.
It is important to remember interindividual variability. The synthesis of these proteins is strictly regulated by polymorphic genes and exhibits marked sex differences, which together explain differences in therapeutic response among patients.