Learn how advances in biomedicine hold the potential to revolutionize drug development, drug treatments, and disease prevention: where are we now, and what does the future hold? This course will present short primers in genetics and mechanisms underlying variability in drug responses. A series of case studies will be used to illustrate principles of how genetics are being brought to bear on refining diagnoses and on personalizing treatment in rare and common diseases. The ethical and operational issues around how to implement large scale genomic sequencing in clinical practice will be addressed. After completing this course, learners will understand 1. The ways in which genetic variants can contribute to human disease susceptibility 2. How to choose among drug therapies based on genetic factors 3. That the functional consequences of the vast majority of genetic variants discovered by modern sequencing are unknown. This course is targeted primarily at physicians 5+ years out of training. Other healthcare providers, medical/health sciences students, and members of the public may also be interested. Course launches January 15, 2016. * The information presented in “Case Studies in Personalized Medicine” is offered for educational and informational purposes only, and should not be construed as personal medical advice. If you have questions or concerns about a medical matter, please consult your doctor or other professional healthcare provider.
Drug Metabolism & Transport
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Case Studies in Personalized Medicine
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UNIT 1: INTRODUCTION TO PERSONALIZED MEDICINE
The first module of this course will focus on introducing the concept of personalized medicine. We will very briefly review fundamentals of genetics as these apply to personalized medicine (DNA structure; RNA; protein structures; function of DNA; coding; DNA variations; types of genetic variants), as well as review statistical concepts and skills important to clinical data analysis (odds ratios, relative risk, P values, multiple testing, sensitivity, specificity, ROCs). In Module 2 we will explore drug actions and reactions as we look closely at the general mechanisms underlying variability in drug responses, drug metabolism and transport, and genetic variability in drug-handling molecules.
Rencontrer les enseignants
Dan Roden, M.D.Professor of Medicine and Pharmacology
Assistant Vice Chancellor for Personalized Medicine
[MUSIC]
Last time, I presented a framework for thinking about how to analyze variability
and drug action, and framework includes the processes of absorption, metabolism,
excretion, distribution, and interaction of the drug with its molecular target or
targets to produce whole organ effects.
And I eluded to the idea that genetics can affect all of those processes, and
so today I'm going to talk a little bit more about how that genetic process works.
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.
So when people develop very high digoxin concentrations,
they have two very serious effects.
One is on the heart, abnormal heart rhythms.
The other one is that their thought processes become disturbed and
their vision becomes disturbed.
And classically, the visual disturbance is yellow halos around lights.
And so, there are people who think the doctor Gachet actually gave
Vincent van Gogh far too much digoxin, and
that's why Starry Night, which you see on this picture, looks the way it does.
He was chronically digoxin intoxicated.
So let me come back to the patient that I discussed with you.
That patient has very high drug concentrations in their blood and that,
presumably, accounted for the toxicity.
When people think about that they say, well, the drugs that he was
getting must have in some way interfered with the way Digoxin is metabolized.
Digoxin is one of those drug that the body just doesn't metabolize.
You absorb it, it hangs around in the blood, and
then it's excreted in the bile in the kidneys.
So it's not metabolized, it's excreted unchanged.
And it turns out that the administration of a long list of drugs
including amiodarone, will interfere with that excretion process.
And it turns out that we now understand the digoxin is moved from one side of
the cell membrane to another by a process called drug transport.
And there's a specific molecule which we call p-glycoprotein
that actually accomplishes that transport.
Amiodarone and
many other interfering drugs interfere with the way p-glycoprotein works.
Digoxin can't be excreted.
The concentrations get high.
The patient develops abnormal heart rhythms.
So that's the way that patient worked, probably a drug interaction.
So let me tell you a little bit more about these drug transport molecules.
This is a picture of what goes on at the intestinal
lumen in the kidney cells.
In the liver cells,
hepatocytes, and in the capillaries of the blood brain barrier.
And at each position, you see a cell and multiple little pieces of alphabet soup.
Each one of those represents a gene, and each gene encodes a drug transporter.
Some of those drug transporters function by taking a drug up
out of the circulation and moving it into a cell.
Some of those drug transporters function by taking a drug that's inside a cell and
squirting it back out again, back out into the circulation, or
back out into the bile, or back out into the kidney lumen into the urine.
So that's the way drug transporters work.
The little black squares highlight the letters MDR1.
MDR1 is the gene that encodes P-glycoprotein,
that very important transport molecule for digoxen.
And you can see that P glycoprotein is expressed in the intestine, in the liver,
in the kidney, and in the capillaries near the brain.
And in each one of those places interfering
with P-glycoprotein function will change drug concentration.
So let me give you two examples of how P-glycoprotein function works
to change the amount of drug delivered to important sites in the body.
This is the first example, and this is how P-glycoprotein works
to change the amount of drug that's ordinarily delivered into the brain.
The picture that you see is a capillary that profuses brain cells.
And what happens is that drugs are taken up into the capillaries and
then transported into the brain cells.
And one of the mechanisms that the brain has of defending itself against drugs is
normal P-glycoprotein function.
So what happens is a drug will get into the capillary cell and
then P-glycoprotein will squirt that drug right back out into the capillary,
limiting the amount of drug that actually penetrates into the brain.
You see that on the top panel.
There's a picture of drug concentrations versus time, and there's high
concentration plasma and very, very low concentration in brain, in green.
Now, if you give a drug that interferes with P-glycoprotein function, or
P-glycoprotein is in some way not quite normal say through genetic variance,
then P-glycoprotein won't accomplish that squirting out function properly, and
the amount of drug that gets into the brain is much, much higher.
You could see that in the over panel where the amount in plasma is about the same,
but the amount in brain is much higher, and
that's why the brain on the bottom is dark green and
the brain on the top is only light green, because the concentrations are much higher
in the lower example than they are in the higher example.
Another example that is very,
very common, quite complicated, is what goes on when we absorb drugs.
So there are many, many drugs that are handled by the body in the following
fashion: the drug is administered orally, and enters the intestinal lumen.
The first thing that it sees is an intestinal cell,
that's this group of three cells down at the bottom of the slide.
The drug is transported into the intestinal cell where one of two or
three things can happen to it.
One is that it can be transported out the other side
through a second drug transport system.
It can be transported back into the intestinal lumen
by P-glycoprotein shown in blue here.
Or it can in fact be metabolized in the intestinal cell, and
once it's metabolized, the metabolites can then be transported back into the lumen,
transported out the other end of the intestinal cell.
Once drugs or the metabolites get out the other end of the intestinal cell,
they enter the portal circulation.
The portal circulation perfuses the liver, and they enter the liver cell.
So again, they can get taken up Into the liver cells by active transport molecules
and then one of two things can happen: they can exit the liver cell or
they can be transported to the bile and
of course the third thing that the liver accomplishes is drug metabolism.
So now we have drugs and metabolites being transported Into the lumen,
into the enterocyte, the intestinal cell, into the hepatocyte, the liver cell,
and being excreted into the bile or making it into the systemic circulation.
So this illustrates the importance of p-glycoprotein as a mechanism for
drug excretion.
And it also illustrates the fact that of the molecules that we take by mouth,
not 100% of them arrive into the systemic circulation.
For some drugs only a very, very small proportion managed to escape
this protective mechanism that the body has and
the body will actually metabolize or excrete a large proportion of drug.
For other drugs, these process are not very important and almost all of the drug
that we give by mouth arrives in the system of circulation.
So p-glycoprotein is one of those very important drug transport molecules, whose
function is to change the amount of drug delivered into the systemic circulation,
the amount of drug delivered into cells, the amount of drug delivered into bile,
into urine, and other important sites of action.
[MUSIC]
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