“When a substance is taken into the body and touches the GI tract membrane, an immediate identification process occurs. What is this thing? And is it safe? If the intestinal wall identifies it as harmful, then it can:
Exclude it; that is, use what is called an efflux pump or an efflux transporter to move the thing out, making sure it does not affect the cell/organism.
Metabolize it; that is, chemically turn it into something else that is not harmful, which is then either used or excreted from the cell/organism. The chemical substances that are thus created are called metabolites.
Attach it; that is, link the substance chemically to a highly water-soluble substance, often glucuronic acid. This creates a new compound that is unable to diffuse through cell membranes. It is then excreted in either urine or feces.
Reduce assisted absorption; that is, inhibit influx transporters. Assisted absorption involves the use of transporter proteins, a.k.a. influx transporters, in the lining of the intestinal wall. These proteins transfer useful substances into the cells of the intestinal wall and from there they are transported to the blood. Influx transporters are strongly active in moving such things as amino acids across the intestinal membrane. One of the most potent is gamma-glutamyltransferase (GGT). It is present in the cell membranes of the intestines, kidneys, bile duct, liver, spleen, heart, brain, and seminal vesicles.
All these responses make it harder for substances to get into the body and affect it. Many pharmaceuticals are considered to be foreign substances and, when these actions take place, up to 85 percent of a pharmaceutical may be inactivated, which is part of the reason doses are so high with some drugs.
Piperine affects all four of those mechanisms that control access to cells. It has particularly strong effects on efflux pumping, metabolization, glucuronic acid attachment, and GGT.
There are a number of efflux transporters. P-gp, or permeability glycoprotein, is one of the more prominent. P-gp is found mainly in the intestinal wall, kidneys, liver, brain, testes, adrenal gland, and uterus. It is also common in cancer cells and a few bacteria. You can visualize P-gp as a barrier lining the intestinal wall and choosing which substances to let into the body and, if so, how much (it also does this at the blood-brain barrier). Piperine significantly reduces the ability of P-gp to block incoming substances.
As a result, if you take piperine or black pepper (or the traditional Ayurvedic blend trikatu), more of the medicinal will pass through the intestinal wall and into the bloodstream. Sometimes, the amount getting into the blood is substantially higher, up to 32 times its levels without piperine. This is why particular care needs to be taken if you are using piperine and are also taking pharmaceuticals. It is also why you should never take piperine with severe infections of the intestinal wall such as E. coli and cholera. Piperine would allow the bacteria to more easily infiltrate the intestinal wall and get deeper into your system.”