Let me start by showing you that drug metabolism is more
complicated than just a drug arriving in the liver and being metabolized.
Drugs are metabolized by specific enzymes in the liver, and
each drug has its own set of enzyme or enzymes that accomplish its
metabolism to other drug metabolites, usually more hydrophilic
than the parent drug that allows the drug to be excreted in the kidney and the bile.
Drug metabolism is traditionally divided into two parts, Phase I and Phase II.
Phase I drug metabolism is the process of drug oxidation.
Hydroxylation, those processes, and
that is accomplished usually by members of the cytochrome P450 superfamily.
We abbreviate that CYP.
So what you see here are many many members of the CYP superfamily, such as CYP2D6.
We call that CYP2D6, or CYP3A4, or CYP2C9, or CYP2C19, and
that's the terminology I'm going to use.
Each one of those enzymes metabolizes one or
more drugs that are important for human therapeutics.
The space that they occupy on the pie chart is proportional to the number
of drugs that we use in clinical practice that that particular enzyme
system metabolizes.
So by far the most important enzyme, metabolizing drugs that we
use in human therapeutics is the CYP 3A4, 3A5, 3A7 family.
Those are three separate enzymes,
all of which accomplish the same kind of drug metabolism.
The next most important is CYP2D6 in yellow.
CYP2D6 actually occupies a tiny proportion of liver enzyme,
but it's very important as a drug metabolizing enzyme.
So that's why it occupies such a large proportion of the pie.
The other part of the pie is phase II metabolism.
Phase II metabolism doesn't change the structure of the drug,
it attaches new molecules to the drug.
And those molecules are acetyl groups, methyl groups, lukeronal groups or
sulfonyl groups, and so the enzymes that accomplish that are called transferases.
They are acetyl transferases, you see NAT1 and NAT2 at the top of the pie chart.
They're glucuronyl transferases, UGTs that occupy a large proportion
of the pie chart, the self anneal transferases in pink.
So those are the enzymes that accomplish drug metabolism, and
the important point in this is that each one of these has genetic variants
in the gene that encodes the particular enzyme that you're looking at.
So there are important variants in CYP3A4,
in CYP2D6, in UGT1A1, in CYP2C9, and
each one of those may be important for variable drug metabolism.
And that in turn can effect response to the drug.
So that's one of the ways in which genetics affects drug responses.
Let me introduce another set of molecules that can also affect the way
the body handles drugs.
Let me introduce them to you by showing a clinical case.
This is a set of electrocardiograms recorded
from the man who was transferred to our hospital from an outside hospital,
because he had recurrent ventricular tachycardia.
That's that very fast, disorganized rhythm on the second, third, and
fourth panels here.
So he had a history of what we call non-ischemic dilated cardiomyopathy,
severe heart disease, and his medications included ramipril, an ACE inhibitor,
Simvastatin, a lipid lowering drug, Metoprolol, a beta blocker, Digoxin,
a drug to increase cardiac contractility, spironolactone,
a diuretic drug, and because of his abnormal rhythms, he had also been treated
with a drug called amiodarone, and that had been given intravenously.
He was having more and more abnormal rhythms, and we didn't understand why,
until someone thought to measure the amount of digoxin in his blood and
he had very, very high digoxin concentration 5.5.
Anything above two is toxicity and
we like to have concentrations around one in most patients who receive the drug.
So that is probably the mechanism of this abnormal rhythm,
but what is it that made his digoxin level get so high?
So let me take a little digression and tell you a little bit about art.
This is one of the last paintings that Vincent Van Gogh painted and
it's a portrait of his doctor, Doctor Gachet.
This painting hangs in a, In a museum of modern art in Paris.
And one of the interesting things about this painting is this flower here.
The flower,
which is shown in the next slide, is actually picture of the flower foxglove.
Foxglove is the flower from which Digoxin is actually extracted.