Ladies and gentlemen,
my name is Kim Brosen.
I'm a professor of
at the University of Southern
Denmark in Odense, Denmark.
I'm going to talk to you about
the clinical significance
of enzyme induction and inhibition.
There is a Danish cartoon
made by a Danish cartoonist
called Robert Storm Petersen.
It shows a physician who hands
a prescription to a patient
and says to the patient, "If this
drug doesn't help, then come back,
and I can prescribe
you something else."
And then the patient
says: "Why don't
I get something else right away?"
And what we're going
to talk about today
is related to this everyday
that the outcome of a
treatment is unpredictable
because patients are different.
Patients are different both
in their pharmacokinetics
and pharmacodynamics because there
are different host factors
that influence the actions of drugs.
Patients live in
And patients are
And these three domains
certainly also influence
differences in drug metabolism.
Drug-drug interactions are something
that can occur when two or more
drugs are given concomitantly.
And what it means is that one
perpetrator drug changes the effect
of another victim drug
in a way which
is not beneficial to the patient.
Usually, drugs are developed
and made in such a way
that the likelihood of giving
interactions with other drugs
So therefore, it's quite
common in clinical practice
that drugs can be combined without
any drug-drug interactions.
Or there can be clinically
unimportant drug interaction.
It's rather unusual that there
are clinically important drug interactions,
which can be
coped with by adjusting the dose
or changing the dose regimen.
And very rarely, drug-drug
interaction is so dangerous
that two drugs cannot be combined.
So the conclusion
on drug interactions is that,
given the number
of possible interactions,
the number of actual
interactions is small.
But it doesn't mean that the problem
of drug interactions is negligible.
Like I said previously,
is a consequence of polypharmacy,
which can be necessary if patients
suffer from more than one illness.
Sometimes it may be
an advantage to treat
the same illness with two or more
drugs attacking different targets.
Or the adverse effect
of one drug can be
dealt with by giving another drug.
So there are many good reasons to
combine drugs in clinical practice.
But of course, we would like to
avoid drug-drug interactions.
What this slide shows
is the way in which
the 200 most commonly used drugs
in the United States of America
70% of all common prescription drugs
are biotransformed in the liver.
And of these 70%,
that means 50% in total
is oxidized by the
cytochrome P450 enzyme system in the liver,
which will form
the focus of this presentation.
In humans, there are 57 CYP
genes and 33 pseudogenes.
They're organized into 18
families and 42 subfamilies.
And the CYP enzymes that
metabolize drugs by oxidation
belong to the families 1, 2, and 3.
What this slide shows is the
localization of the cytochrome P450 enzymes
in the membrane of the
smooth endoplasmic reticulum where
the drug-metabolizing enzymes,
together with a co-enzyme, which is
a reductase NADPH. And oxygen is
able to insert one atom of oxygen
into the molecule of
thousands of different drugs,
which in this way, becomes more
polar and, usually, less active.
There are two main types of
drug-drug interactions in relation
to drug metabolism.
The one type is called the
which may occur when two drugs
that are both substrates
of the same drug-metabolizing
are given at the same time to patients.
The two drugs may compete to
binding to the active site.
And this may impair the elimination
of at least one of the drugs.
Such interactions occur rapidly.
They wear off rapidly.
It's a direct chemical
effect of one drug
on the metabolism of another drug.
And it's something which
can be studied in vitro.
The consequences are that
drug concentration in blood
may increase due to its
The opposite, so to speak, type of
interaction is called induction.
And it's a biological phenomenon
that starts gradually,
wears off gradually, and usually
is due to increased protein synthesis.
And something which
cannot be studied in vitro,
but rather requires the
experiments in animals or man.