Drug - Nutrient Interactions
and HIV
by Joanne Maurice
The science of drug-drug interactions
and drug-nutrient interactions has advanced and improved in
the past few years. There are several interactions and mechanisms
that take place that can affect how well a drug is or is not
absorbed, and many of these factors we have no control over.
Drugs can be absorbed differently depending on race, age,
gender, weight, and metabolic rates. Pharmaceutical companies
have spent billions of dollars running drug trials to discover
the most effective methods of taking a medication that will
result in the best absorption and with the fewest adverse
side effects.
Once a pill is ingested, it
goes into the gut, dissolves and is absorbed through the intestinal
tract. From this point on, what happens to the drug and how
it is measured forms the basis for the various recommendations
providers, pharmacists and dietitians give to their clients.
Foods can have an effect on a drug by increasing, decreasing
or accelerating its absorption or metabolism. The composition
of a food, or meal, can affect the bioavailability of a medication
by affecting acid level in the stomach, increasing or decreasing
transit time through the gastrointestinal (GI) tract, or inducing
or inhibiting the different metabolic enzymes in the intestine
and liver. Adhering to diet recommendations and timing of
meals can make the difference between a drug having the most
effect, or helping to decrease the side effects that can come
with the medications.
To understand what is happening
after a drug is ingested, a little background and some definitions
are needed. Pharmacists and drug companies often cite the
Cmax of a drug. This is the maximun concentration reached
by a drug, where the rate for a drug being absorbed into the
plasma is the same rate that it is being eliminated from the
plasma. Cmin, or minimum concentration, is when a drug is
at its lowest concentration, often just before the next recommended
dose. Area under the curve or AUC, is a way of measuring the
exposure to a drug during a full dosing interval. AUC is often
viewed as the best way to see if a drug is working. Cmin is
often used to predict the efficacy of the drug, where Cmax
is associated with the severity and frequency of side effects.
Many studies and drug trials
will list the effect that a single dose of another drug or
nutrient has on the medication in question. A steady-state
response, where there are no more changes after repeated doses,
may be a more fair indication of an interaction. The effect
of grapefruit juice on the absorption of Crixivan (indinavir)
is one example where the effect seen during a single dose
was different during steady-state conditions.
Once a drug is absorbed, it
must be metabolized (broken down by the body’s system).
There are several systems in the body, one of the best known
is the cytochrome P450 (CYP450) system. Within this system
there are several isoforms that can be induced or inhibited
by a multitude of drugs and some nutrients. The level that
a drug reaches in the plasma can be determined by the extent
to which these isoforms are induced or inhibited. St. John’s
wort is an example of such a drug-nutrient interaction. It
can compete with Crixivan for the isoform CYP3A4 system, reducing
significantly the amount of Crixivan available to fight the
virus. The AUC for Crixivan is reduced by about 60% with St.
John’s wort, prompting the warning of increased risk
of drug failure and viral resistance due to suboptimal levels
of Crixivan in persons who were also taking St. John’s
wort.
Grapefruit juice deserves
its own mention as a having a significant effect on the isoform
CYP3A4 of the CYP450 system. The components of the flavonoids
found in grapefruit juice have various degrees of activity
on CYP3A4. There are other components besides the flavonoids
in grapefruit juice that can have an effect on the CYP3A4
activity. The same does not seem to hold true for other citrus
fruits such as lemon, limes and oranges. The effect that grapefruit
juice has can be very different depending on the PI or other
medication involved. For Fortovase (saquinavir soft-gel),
the grapefruit juice significantly increases its bioavailability.
Grapefruit juice, in the first studies of Crixivan, indicated
a significant decrease in the bioavailability of Crixivan
with a single dose of grapefruit juice. However, when studied
during steady-state conditions, the adverse effect on Crixivan
was not seen.
Using the AUC, it was found
that a high fat meal increased the bioavailability of saquinavir
by 670%, Viracept (nelfinavir) by 200 to 300%, and Norvir
(ritonavir) by 15%. There are thoughts that not taking these
medications with a meal providing adequate fat could be the
reason for some treatment failures. Every study seemed to
define high fat differently, but for the most part a high
fat meal was along the order of 50 grams of fat per meal.
For those of you without your fat gram counting books, that
works out to be a burger and fries kind of meal, a large muffin,
or a significant amount of chips. On the other side of the
coin, Crixivan, without the Norvir booster, needs to be taken
with a meal containing essentially no fat. Agenerase (amprenavir)
can be taken with food, but should not be taken with the same
kind of high fat meal that boosts the efficacy of saquinavir.
Sustiva (efavirenz), like Agenerase, should not be taken with
a high fat meal, because the fat increases the absorption
and increases the magnitude of the side effects.Due to the
presence of Norvir, Kaletra (lopinavir/ritonavir) should also
be taken with food to increase its bioavailability and decrease
intra- and intervariability.
Garlic is also being studied
for the effects it may have on HIV medications. Touted for
its immune enhancing properties, and its safety as a supplement,
garlic is beginning to be studied for potential adverse effects
on medication metabolism. It appears to decrease the AUC significantly
for saquinavir. There was a small decrease when looking at
Norvir, but it was not significant.
The lesson here is that don’t
assume that it is okay to take medications without regard
to the instructions given by qualified HIV health care providers.
There are reasons when doctors and service providers inform
you that a medication needs to be taken with more than just
a cup of coffee or a banana. It’s also not safe to assume
that just because a product is “natural” or an herb,
that there are no potential side effects or interactions with
other medications. The process of metabolism is extremely
complicated and the same substrate can be both an inhibitor
or inducer of the process. So stay tuned, the science is young,
and more answers are yet to come.
Joanne Maurice can be contacted
via email at jmaurice@u.washington.edu.
References are available from author upon request.
|
