Definition:
Drug transporters are specialized proteins embedded in the cell membrane that play an essential role in controlling the absorption, distribution, metabolism, and excretion (ADME) of drugs and other xenobiotics in the body.
They act as gatekeepers, facilitating the movement of substances into or out of cells across the cell membrane, either from the blood into the cells (influx transporters) or from the cells into the blood (efflux transporters).
Their activities can influence the pharmacokinetics, efficacy, and side effects of drugs.
1. Protein Structure: The structure of drug transporters, as with many other proteins, is largely determined by their amino acid sequences. Most of these proteins are transmembrane in nature, which means they span the cell membrane, with regions both inside and outside the cell.
2. Functionality by Conformational Change: Drug transporters often function by undergoing conformational changes, triggered by the binding of a drug molecule. This change in shape enables the transporter to move the drug across the cell membrane.
3. Classification: Drug transporters can be divided into two main superfamilies based on their structure and mechanism of action: ATP-binding cassette (ABC) transporters and solute carrier (SLC) transporters. ABC transporters, like P-glycoprotein, utilize ATP hydrolysis to drive drug efflux against a concentration gradient. On the other hand, SLC transporters, like OCT1, facilitate drug influx often driven by ion gradients.
4. Substrate Specificity: Each drug transporter has a unique range of substrates it can transport. Some transporters are relatively specific, interacting with a small number of similar compounds, while others are more promiscuous and can interact with a wide range of structurally diverse compounds.
5. Impact on Drug Pharmacokinetics: The function of drug transporters greatly affects the pharmacokinetics of a drug, which includes absorption, distribution, metabolism, and excretion (ADME). Variations in the activity of these transporters can cause differences in drug response between individuals.
6. Tissue Localization: Different drug transporters are expressed in different tissues in the body. For example, P-glycoprotein is expressed in high amounts in the liver, kidneys, intestine, and brain, where it helps to protect these organs from toxic compounds.
7. Pharmacogenomics: Genetic variations, such as single nucleotide polymorphisms (SNPs), can alter the function of drug transporters and consequently influence drug response. Pharmacogenomic studies aim to understand these genetic influences to allow for personalized drug therapy.
8. Drug-Drug Interactions: Some drugs can inhibit or induce the function of certain drug transporters. This can lead to drug-drug interactions, where the presence of one drug affects the absorption, distribution, metabolism, or excretion of another.
9. Involvement in Drug Resistance: Overexpression of certain efflux transporters, like P-glycoprotein, is a common mechanism of multi-drug resistance in cancer. These transporters pump chemotherapeutic drugs out of the cancer cells, reducing their efficacy.
10. Role in Blood-Brain Barrier: Drug transporters play a significant role in regulating the passage of drugs across the blood-brain barrier. Overexpression of efflux transporters in the barrier can limit the effectiveness of drugs intended for central nervous system targets.