Pharmacology
Summary
The P-glycoprotein (Pgp) is a vital transmembrane protein consisting of two transmembrane domains and two cytoplasmic nucleotide-binding domains. It operates by utilizing two ATP molecules to actively export substrates from the cell, converting both ATP molecules to ADP in the process. Pgp primarily acts as a protective mechanism against foreign entities, such as toxins and drugs, by pumping these xenobiotic molecules out of cells, ensuring their elimination. These efflux pumps are strategically positioned in crucial areas within the body, like the GI tract, liver, and the blood-brain barrier (BBB). Certain medications, including digoxin and ciclosporin, are recognized as Pgp substrates and are effluxed by this protein. However, drug interactions can modify Pgp activity. Medications like macrolides, amiodarone, and verapamil inhibit Pgp, potentially elevating the serum concentrations of Pgp substrates. Conversely, inducers like St John’s wort and rifampin can reduce serum concentrations of Pgp substrates.
In the context of drug pharmacokinetics, enterohepatic recycling is a key process. This mechanism involves a drug undergoing metabolism in the liver, followed by its excretion into the gut via bile. Here, the intestinal flora metabolizes the drug into its free form, which is then reabsorbed into the small intestine, and subsequently redistributed to the liver and tissues. Such recycling extends the duration of action for certain drugs, including some NSAIDs, opioids, and hormones. Importantly, antibiotics can disrupt enterohepatic recycling. By targeting and killing the intestinal flora, they reduce the deconjugating enzymes, leading to diminished drug reabsorption and serum drug concentration. In such situations, dose adjustments may be necessary to compensate for the reduced enterohepatic recycling.
Lesson Outline
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FAQs
P-glycoprotein (Pgp) serves as a protective mechanism against foreign molecules such as toxins and drugs. It accomplishes this by actively pumping xenobiotic molecules out of cells to be eliminated from the body. Pgp is commonly found in critical areas of the body, including the GI tract, liver, and blood-brain barrier.
Certain commonly used drugs, such as digoxin and ciclosporin, are substrates for Pgp, meaning they are effluxed or expelled by Pgp. Some drugs also inhibit Pgp, leading to an increase in serum concentration of the Pgp substrates, while other drugs can induce Pgp, resulting in a decrease in serum concentration of Pgp substrates.
Pgp can confer multidrug resistance to cancer cells by reducing the accumulation of chemotherapeutic agents inside the cell. This process can increase the risk of therapeutic failure.
Enterohepatic recycling involves this process: drug metabolism by the liver, excretion of the drug via bile into the gut, followed by metabolism to the its free form by intestinal flora, and finally reabsorption in the small intestine and distribution of the active drug back to the liver and tissues. This process can extend the duration of action of certain drugs, like NSAIDs and opiods.
Antibiotics can kill intestinal flora, leading to a decrease in deconjugating enzymes. This decrease can in turn lead to a reduction in drug reabsorption and lower serum drug concentration. As such, it may be necessary to adjust drug doses to make up for the reduced enterohepatic recycling resulting from antibiotic use.
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