While
it appears to be an overly basic question, drug interactions can be very
complex and the mechanisms by which they occur can vary greatly. Some
clinicians may believe that most, or all, drug interactions can be predicted or
explained by evaluating the cytochrome P450 (CYP450) enzyme profiles of the
drugs in question. This is clearly not the case and can result in the
coadministration of a dangerous or inappropriate combination of two or more
medications. In fact, many drug interactions cannot
be explained by solely evaluating the CYP450 profile of two medications.
As a result, clinicians need to be aware of the other common pathways which
result in drug interactions.
The
main categories or classifications of most clinically relevant drug-drug
interactions are pharmacokinetic, pharmacodynamic, or a combination of the
two. Simply stated, a pharmacodynamic drug interaction results in an
exaggerated biological or physiologic response when two interacting medications
are coadministered. A great example of this type of drug interaction is
the coadministration of a nitrate and one of the type 5 phosphodiesterase
inhibitors (such as sildenafil (Viagra)) and their synergistic effects on blood
pressure.
A
pharmacokinetic drug interaction occurs when concomitant use of medications
results in changes in one or more of the following parameters: absorption,
distribution, metabolism, or elimination. Factors influencing absorption include
the acidity of the environment and the pKa of the drug, the presence of other
medications that could chelate with the drug in question, drugs that may affect
gastric emptying and intestinal transit times, and the presence/activity of
influx and efflux transporters (such as Pgp, OATP, MRPS, BCRP, etc) in the
lumen of the intestine. In fact, influx and efflux transporters are
emerging as a major contributors to many drug interactions, especially those
that cannot be explained by the CYP450 system. These transporters not
only reside in the gastrointestinal tract, but are also present in the liver,
gallbladder, and kidneys, where they can influence the distribution and
elimination of many medications. In addition to being substrates of
these transporters, they can also affect their activity. This is similar to the
mechanism by which many medications affect the CYP450 enzymes. The last
two mechanisms for drug interactions are related to a change in the chemical
structure and activity of the medication itself. These occur during phase
I and phase II pathways of metabolism and elimination. Within phase II
pathways, drug interactions via the glucuronidation pathways are most common.
Lastly, phase I metabolic pathways occur through the CYP450 enzyme
system. This large and diverse group of enzymes is found primarily in the
liver, but may also be found in the GI tract and the kidneys.8 As eluded
to above, medications may be substrates of these enzymes as well as inhibitors,
inducers or a combination of these (making drug interactions even more
complicated). Upcoming newsletter issues will provide further details on
each of these pathways.
Before
leaving this brief overview of the mechanisms of drug interactions, it is
important to recognize an emerging area of medical science. The
complexity of drug interactions is complicated further by the fact that each,
if not all, of these pathways or mechanisms are under the influence of each
patient's genome (genetic makeup). Even the simplest forms of genetic
variations, such as single nucleotide polymorphisms, can significantly alter
the biologic activity of one of these pathways.
