Drugs are mainly eliminated from the body by two organs, the liver and the kidney. The kidney rids the body of some drugs in the urine. The liver rids the body of some drugs in the bile via the gallbladder. Both the kidney and the liver sometimes need to metabolize, or chemically change, drugs into forms that are more easily eliminated from the body.
The liver acts as a gatekeeper between the gastrointestinal tract and the rest of the body because it is the first major organ to receive blood (and the drugs absorbed into the blood) from the intestines. In fact, the liver can metabolize some drugs so quickly that after taking one of these drugs by mouth, only a small fraction of the drug is left to travel through the body. But how do your liver and kidneys “know” how to metabolize drugs they’ve never seen before? Humans didn’t suddenly develop ways to eliminate or modify drugs. Rather, through the course of our evolution as a species, our livers now have a large family of enzymes (proteins that modify or metabolize chemicals) to deal with a range of substances. Probably originally developed and retained to deal with foreign chemicals in food or the environment, these enzymes now also serve to break down drugs.
The enzymes come in many different types but the largest family is known as the cytochrome P450’s (CYP450). More than a thousand CYP450’s have been identified in various species; humans alone have more than 50 distinct genes for CYP450’s. These enzymes are very old and have been conserved in the evolutionary sense, meaning that many plants and bacteria have similar enzymes to those now found in humans. Several individual enzymes metabolize the majority of drugs available today. The CYP450 enzymes that are most commonly involved in drug metabolism are CYP3A4, CYP2D6, CYP2C9, CYP2C19, CYP1A2, and CYP2E1. CYP3A4 is the most important enzyme in drug metabolism due to its abundance in the liver and the intestine and its ability to modify many different types of chemicals and drugs. CYP3A4 is involved in the metabolism of more than 60% of all drugs that are on the market today.
Inhibition of metabolism. When a drug blocks or inhibits one or more of these CYP450 enzymes, it interferes with the elimination of drugs that are normally metabolized by the blocked enzyme(s). If a drug cannot be metabolized, it is not eliminated as quickly as it should be and can accumulate in the bloodstream, resulting in higher blood levels of the drug. The blocked drug also stays in the bloodstream longer than expected. Both of these situations can lead to trouble.
The once-popular antihistamine terfenadine (Seldane) was removed from the U.S. market because it caused potentially fatal heart rhythms when given in combination with drugs that block its metabolism. It was found that terfenadine was normally broken down in the body by CYP3A4, but when a CYP3A4-blocking drug such as ketoconazole (an antifungal drug) was given at the same time, the levels of terfenadine were both higher in the bloodstream and higher for a longer time. The high levels caused the heart problem, and because it was difficult to prevent the potentially harmful mixture of drugs, terfenadine was removed from the market in 1998.
Induction of metabolism. Some drugs can increase the levels of a CYP450 enzyme in the body by interacting with the genes for that enzyme. The increased levels of enzyme serve to metabolize drugs faster than normal, which reduces the blood levels of medicines metabolized by that enzyme, making them less effective. This process is called induction, and the drugs that serve to increase the amount of enzymes are called inducers.
Inhibition of excretion. The diabetes drug metformin, on the other hand, is not metabolized by enzymes and is eliminated unchanged in the urine. This means that it is not susceptible to other drugs that inhibit CYP450 enzymes. However, metformin concentrations in the body can be increased by drugs that inhibit its excretion from the kidneys, such as cimetidine (Tagamet).