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
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
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
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
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).