Treatment Review, Spring 1998

The liver is a large organ, located just below the lungs on the right side of your body. The liver regulates the processing of nutrients and vitamins from the food you eat, both storing nutrients for later use and changing nutrients into forms that the body can use for energy. This is part of the process known as metabolism. The liver has many other important jobs: cleaning dead cells out of the blood, processing or metabolizing drugs, getting rid of toxic substances (alcohol, for example), producing bile (a substance that helps the body digest fat) and making factors that help your blood clot. Medical words for the liver usually start with hepat-, for example a doctor that specializes in the liver is called a hepatologist.

How Are Drugs Processed? Most prescription drugs are absorbed in the small intestine. This means that the drug must be able to survive travelling through your stomach. From the small intestine the drug is absorbed into the blood and travels to the liver through the portal vein. The drug must travel through the liver so that it can be processed or metabolized by the body. Metabolism means breaking down the drug for distribution around the rest of the body and, in the end, clearance or excretion from the body. The liver may form metabolites, or changed chemical versions of the drug, as part of this process. Some drugs are almost completely gotten rid of the first time they travel through the liver. This is called first-pass metabolism. The problem with the first available protease inhibitor, saquinavir (Invirase), was that it was almost totally cleared from the body by first pass metabolism. In fact, only a measly 4% of the Invirase that a person swallowed made it through the liver into the bloodstream and to the rest of the body. The idea behind the new version of saquinavir, Fortovase, is to prevent some of this first pass metabolism so that more drug makes it to the rest of the body.

Some prescription drugs do not get broken down in the liver. The nucleoside analog drugs (AZT, ddI, ddC, d4T, 3TC) mainly travel through the kidneys. Although these drugs are not metabolized by the liver, the liver sometimes hooks them up with other chemicals so they can dissolve in water more easily and therefore be gotten rid of in the urine.

The Cytochrome p450 System So what actually breaks down the drugs that are metabolized by the liver? Most of this work goes to a group of more than 25 related enzymes called the cytochrome p450 system. Enzymes are proteins that perform certain jobs in the body. The p450 enzymes do most of their work in the liver, but there are also p450 enzymes in the small intestine that can begin the work of drug metabolism before a drug even reaches the liver.

While the p450 enzymes do a good job of breaking down drugs, there is a potential problem with this system. The activity of the p450 enzymes can be affected by the very drugs they are metabolizing. Some drugs increase the activity of p450 enzymes. These drugs are called inducers. When there is more p450 enzyme activity because of an inducer, any drug metabolized by that enzyme is going to be metabolized faster. This means that less of the drug will get to the rest of the body where it's needed. For example, the anti-tuberculosis drug rifampin is a strong inducer of p450 enzymes. Other drugs metabolized by these p450 enzymes can be cleared from the body too fast if they are taken with rifampin. Protease inhibitors are among the many drugs cleared too fast from the body when taken with rifampin, so these drugs should not be used together. This is an example of a drug interaction.

There is also another kind of drug interaction that can happen in the p450 enzyme system. Different drugs can compete to be broken down by the same enzyme. The protease inhibitor ritonavir (Norvir) is a good example of a drug that competes for several different p450 enzymes in order to get metabolized or broken down. Ritonavir usually wins the competition for metabolism when other drugs are also trying to get metabolized by the same p450 enzyme. What's the result of this? Any other drug has to wait to get cleared from the body until the p450 enzyme is finished with ritonavir. While the drug is waiting to be cleared, the drug levels in the body get higher and higher. This is another example of a drug interaction. This effect also gets called p450 inhibition.

One example of this kind of interaction is with the commonly used antihistamine drug Seldane. Ritonavir competes for the p450 enzyme that usually clears Seldane from the body. The result is that Seldane levels get higher and higher as the drug gets backed up in the body because ritonavir is blocking (also called inhibiting) its normal metabolism. High levels of Seldane are very toxic and are known to cause potentially fatal changes in heart rhythm. This example shows how dangerous drug interactions can be. In fact, Seldane was recently taken off the market because of this potential danger.

Occasionally, however, drug interactions can be used to produce good effects. The reason that the protease inhibitors ritonavir (Norvir) and saquinavir (Invirase, Fortovase) sometimes get prescribed together is because of a useful interaction. Just like the above example with Seldane, ritonavir competes for the p450 enzyme that usually metabolizes saquinavir. As a result, saquinavir levels in the blood get much higher than normal. Because saquinavir is usually not well absorbed, this interaction is seen as a good thing - the higher levels of saquinavir produce stronger anti-HIV effects. The dose of saquinavir given with ritonavir is much lower than the standard dose because of this interaction.

Some drugs can both induce, increasing the activity of p450 enzymes, and also compete for those enzymes with other drugs. Again, ritonavir is a prime example of this double effect. Ritonavir induces the enzymes that helps clear the drug methadone from the body. Ritonavir itself is not metabolized by the same enzymes and so it does not compete with methadone to be metabolized. The end result? Ritonavir lowers methadone levels (see In The News, Page 15).

In most other cases, although ritonavir induces extra production of p450 enzymes, it hogs (competes for, and wins) most of these extra enzymes for its own metabolism. The end result? Ritonavir raises the levels of other drugs (such as Seldane and saquinavir) that need these p450 enzymes in order to be cleared from the body.

Protease Inhibitors and NNRTIs As a class of drugs, protease inhibitors usually compete more than they induce - therefore they are more likely to increase levels of interacting drugs rather than reduce them. The most dangerous interactions are with the antihistamine drug astemizole (Hismanal), the digestion/heartburn drug cisapride (Propulsid), the sedatives triazolam (Halcion) and midazolam (Versed) and a group of drugs known as ergotamine derivatives. These drugs cannot be taken with any of the four approved protease inhibitors: indinavir (Crixivan), nelfinavir (Viracept), ritonavir (Norvir) and saquinavir (Fortovase). Additional restrictions may apply to each individual protease inhibitor - particularly ritonavir, which competes for p450 enzymes more than other protease inhibitors.

The only available protease inhibitors that can also induce p450 enzymes are ritonavir (Norvir) and nelfinavir (Viracept). These drugs can therefore reduce the levels of some other drugs, such as the oral contraceptive ethinyl estriadol (Ortho Novum) and methadone (see In The News, page 15).

The latest class of anti-HIV drugs are called non-nucleoside reverse transcriptase inhibitors (NNRTIs). This class includes the approved drugs nevirapine (Viramune) and delavirdine (Rescriptor), along with the experimental drug efavirenz (Sustiva, DMP266) which is currently available through an expanded access program. Unfortunately, NNRTI drugs are also processed by the p450 enzyme system. Unlike protease inhibitors, nevirapine (Viramune) and efavirenz (Sustiva) usually induce more than they compete - so they are more likely to reduce levels of interacting drugs rather than increasing them.

Delavirdine (Rescriptor) seems to work the other way, blocking the metabolism of other drugs similar to a protease inhibitor - in fact many of the drugs you can't take with protease inhibitors - like Hismanal for example - you also can't take with delavirdine.

What Does It All Add Up To? While the above article covers some of the complicated factors involved in drug interactions, we can't list every possible interaction that can happen. Every time you're prescribed a drug, it's important to think about any effect it might have on other drugs you're taking. It's often a good idea to fill a bag with all your medications and take them to your main medical provider to make sure that there aren't any interactions you need to worry about. There can even be interactions with herbs, supplements and foodstuffs like grapefruit juice. If you have several different providers that cover areas of your care - a therapist, infectious disease doctor, gynecologist and primary care doctor, for example - make sure that everyone knows what drugs you're being prescribed so that they don't prescribe an interacting drug by mistake.

Illegal (sometimes called illicit) drugs can also interact with prescription drugs. The protease inhibitor ritonavir can also block the metabolism of the recreational drug ecstasy (MDMA, X). Very high levels of ecstasy in the body can be toxic. There has been one report from England of a death caused by this interaction. There may be similar potential for interactions with ketamine (Special K). The next issue of Treatment Review will contain a full report on what is known about potential drug interactions with illicit drugs.

Interaction Ground Rules: There are useful ground rules when it comes to drug interactions. If you take even just one dose of a drug that induces activity of p450 enzymes, it can take several days for p450 enzyme activity to return to normal. For example, if you finish a course of TB (tuberculosis) treatment with rifampin, you wouldn't want to start a protease inhibitor the next day - there would still be extra p450 enzyme activity and this would clear the protease inhibitor from your body too fast.

When it comes to drugs competing for the same p450 enzymes, the effect only lasts until the drug is cleared from the system. This is an important difference, because it may mean that some minor drug interactions can be lessened simply by taking the drugs at different times. This is currently being investigated in a study of the protease inhibitor Crixivan and the antibiotic rifabutin (Mycobutin).