Effects of liver enzymes

After being absorbed, most drugs pass to the liver where a portion of the dose may be broken down or modified by enzymes (see below). The most serious drug interactions are likely to be related to the way in which some drugs are processed (or metabolised) in the liver by substances called cytochrome P450 (CYP450) enzymes, or isozymes.

These enzymes are found within the cells that make up the liver. Many different enzymes have been identified; however, researchers have recognised some that are more important than others in processing drugs. These enzymes work by converting the drug into a slightly different form. Other enzymes may then convert the oxidised drug into a water-soluble form that can be readily excreted in the urine. Each individual CYP450 enzyme is given a three-character name, such as CYP2B6 or CYP3A4.

Due to their inherited genetic make-up, some people may produce higher or lower than average amounts of specific CYP450 enzymes, which may account for person-to-person variations in response to treatments. People with naturally high levels of a certain CYP450 enzyme may break down a drug faster than average, thus not achieving high enough levels of the drug in their bodies to be effective. Likewise, people with naturally low levels of a specific CYP450 enzyme may metabolise a drug slower than average, allowing the drug to reach unusually high levels in their body. 

For example, recent evidence has suggested that HIV-positive patients who have altered CYP2B6 levels may handle the NNRTIs (such as nevirapine and efavirenz) somewhat differently than those with normal levels. Drugs resulting in significant drug interactions can also have the effect of increasing or decreasing CYP450 activity. The NNRTI and PI classes of antiretroviral are particularly important in this respect because they not only affect the activity of CYP450, but are also processed by it.

Take the example of a person taking two treatments, Drug A and Drug B. If Drug A causes a reduction in the activity of a specific CYP450 enzyme, that may make it harder for the body to break down Drug B, leading to an increase in blood levels of Drug B. Similarly, if Drug A causes an increase in the level of a specific CYP450 enzyme, that might help the body to metabolise Drug B more quickly, leading to lower blood levels of Drug B. 

The use of low-dose ritonavir is an example of this type of drug interaction. Ritonavir reduces the activity of the CYP3A4 isoenzyme and this results in increased blood levels of other drugs being taken that are also processed by CYP3A4. This interaction is used to good advantage by dosing other protease inhibitors with small amounts of ritonavir, boosting both the amount of bioavailable drug in the system and the length of time it is active.  

While the use of ritonavir in this example is exploited, drug interactions through the CYP450 enzyme system may not always be so favourable. For example, St Johns wort increases (or induces) several CYP450 enzymes used to metabolise key anti-HIV drugs. This may lead to low levels of drugs such as indinavir, nelfinavir (Viracept), saquinavir (Invirase), nevirapine (Viramune), and efavirenz (Sustiva). Consequently, the use of St Johns wort is not recommended in patients also taking these drugs.

Other interactions occur when someone is taking two drugs which are both broken down by the same CYP450 enzyme. In effect, there may not be enough of the enzyme to break down both drugs efficiently and both drugs ‘compete’ for the same enzyme. This results in one or both of the drugs reaching unusually high levels in the body.

In cases where researchers have identified which of the CYP450 enzymes are involved in breaking down specific drugs, or which drugs induce (increase) or inhibit (decrease) the effects of specific enzymes, it allows them to predict when an interaction between two drugs is likely to happen. In the absence of formal studies, this insight is helpful in forecasting potential interactions.