It
is well known that the cytochrome (CYP) P450 enzyme system is involved in drug
metabolism of many medications used in clinical practice and have been
implicated in the causing clinically relevant drug-drug interactions.(1,2)
There are a number of CYP450 enzymes involved in mediating drug interactions
and commonly include CYP1A2, 2C9, 2C19, 2D6, and 3A4.(1) Of these CYP
enzymes, CYP3A4 is not only the most prevalent CYP enzyme in the liver, but is
used by more than 50% of medications on the market for their metabolism and
elimination from the body.(1) In addition, the CYP3A4 activity can be
induced (or accelerated) or it can be inhibited (decreased), thereby changing
the drug concentrations in the body.(1) As it relates to this newsletter
issue, the inhibition of CYP3A4 can result in the accumulation drug
concentrations that can put the patient at increased risk for side effects and
possible toxicity.
A
number of medications are known to be inhibitors of CYP3A4, but they differ in
the degree of inhibition they have on the enzyme and metabolism of substrates
with a high degree of dependency on CYP3A4.(1) As such some inhibitors of
CYP3A4 are viewed or known by clinicians to be "strong or potent
inhibitors" or "mild to moderate inhibitors" of 3A4.
What
determines the classification of a medication to be one of these types of
inhibitors?
A number of governmental agencies in collaboration with the U.S. Food and Drug
Administration (FDA) suggest that CYP3A4 inhibitors be classified based on
their in-vivo fold-change in the plasma area under the curve (AUC) of oral
midazolam or other specific substrate of CYP3A4 when coadministered with
another medication.(2) Midazolam is primarily listed as an ideal substrate
because of its specificity as a substrate to only CYP3A4 for its metabolism.(1,3)
Therefore, any medication known to inhibit CYP3A4 will result in an increase in
the AUC of midazolam. An inhibitor of CYP3A4 is classified as a weak
3A4 inhibitor if the AUC of oral midazolam or other specific 3A4
substrate is increased by 1.25 and 2-fold or results in a 20-50% decrease in
its clearance.(2) It is classified as a moderate 3A4 inhibitor if
the increases in AUC for oral midazolam or other specific 3A4 substrate are increased
between 2- and 5-fold or results in a 50-80% decrease in its clearance.(2)
Lastly, the medication is classified as a strong 3A4 inhibitor when
it increases the AUC of oral midazolam or specific 3A4 substrate by 5-fold or
higher or results in a greater than 80% decrease in its clearance.(2)
Knowing
this information about a particular medication can help the clinician predict
the potential impact of coadministering two interacting medications on the
patient and/or healthcare system. In addition, this is important for
understanding why some drug-drug interactions cause a greater degree of adverse
events than some others.
