D tears the introduction. Millie, thank you very much for the invitation to come and give this talk.
The title you can see on the slide is Millie's title. My title now, in terms of the work,
is called the NHS Chair of Pharmacogenetics. I certainly don't want this to be self-promotional.
What I'm trying to do is to tell you what Pharmacogenetics is, what we are trying to do
in terms of reducing side effects from drugs. But we have a lot of work to do in this area
yn ysgol yng Nghymru.
Mae'n ffysiwn, sy'n dr Mildlton,
ac rwy'n gwybod y clynig
o'r cyfnoddau cyfnoddau
o'r cyfnoddau cyfnoddau.
Ac, cyfnoddau cyfnoddau
o'r cyfnoddau cyfnoddau,
ac ydych chi'n cyfnoddau
o'r cyfnoddau,
rwy'n gwybod i'r cyfnoddau
o'r cyfnoddau
o'r cyfnoddau
o'r cyfnoddau
ac yn ymdweud
y dyma i gyfer y casio'n trat
o'r cyfnoddau
ac os yw'r cyfnoddau
o'r cyfnoddau
ac mae 4 drwy'r clyfrydau
sax novaeth
o hynny'n cydewid.
Ydw i'n gweithio'n gwybod
o'r cyfnoddau o'r cyfnoddau
oherwydd yr ysgol gyda'r cyfnoddau
o'r cyfnoddau o'r cyfnoddau
o'r cyfnoddau.
A'r cyfnoddau o'r cyfnoddau
o'r cyfnoddau o'r cyfnoddau
yn terms of treating the patient.
So what I am doing, when I am treating that particular patient who has been
referred to me, is personalising treatment to that particular patient.
So I'm individualising doses, I'm individualising which drug that they should take.
So personalisation should be happening with every physician, every doctor who
treats patients with drugs and that's been around for a long time.
Clearly what we're doing is trying to use the best drug for the patient according
to what is known at the moment from trials, from other kinds of studies and what's
in terms of guidelines.
However, this is not perfect and everybody appreciates it's not perfect and the
reason that it's not perfect is that we can't predict which patient is going to
respond to that drug in a beneficial way.
For example, in depression it's said that maybe 30% of patients respond to the
first drug you give them, 30% respond slightly to the drug and 30% don't
respond at all and so then you have to go and find another drug to see whether
they respond and you have the 30, 30, 30 split again.
We also don't know which patients are going to develop side effects to medicines
and we're trying to develop methods to be able to overcome some of these side
effects and predict them beforehand.
And this is seen in some of the data that we've published that many patients
still develop side effects and clearly this is important to be able to develop
mechanisms to be able to reduce these side effects so that we can treat our
patients better, so that we can maximise benefits from drugs and minimise harms.
So we did this big study in Merseyside in two hospitals where we looked at
in a prospective fashion at about 19,000 patients and this was over six months
and we found that 1224 patients, that was 6.5% of patients were admitted to our
two hospitals directly because of adverse drug reactions and when we extrapolated
this to the NHS bed base we found that this probably cost the NHS about half
a billion pounds per year and those are huge figures and what we need to do is
to be able to bring those figures down and try to improve that and what we've
been trying to do in Liverpool within the research group that I work in is really
to try to quantify and evaluate what is going on at the moment so that we can
bring in intervention strategies to improve this and reduce the harms associated
with medicines.
And so when I prescribe, what I'm doing is clearly trying to maximise the
benefits of any drug and minimise the harms and unfortunately this doesn't occur
all the time as I've just told you.
So the many reasons why harm benefit balance in individual patients may not
be optimal.
One is genetic and I'm going to spend most of my time on the genetic factors.
I'm going to tell you exactly what pharmacogenetics is but I don't want to
say that everything is related to genetics, a lot of maybe environmental
clinical factors and just a couple of them are listed on the slide here.
For example, some patients forget to take the medicines and some patients come to
my clinic, hypertension clinic and say doctor I forgot to take the drug on one
day so the next day I took two tablets and that does happen still very
frequently and clearly that can predispose you to side effects in one way or
another.
One issue is poor prescribing by the doctor and I think Dr Simon Maxwell will be
presenting on the kind of steps which are going on to improve the education of
prescribers and that is very important and that clearly needs to continue at the
graduate level and that needs to continue throughout the doctor's life or
anybody who's a prescriber because you know that nurses and pharmacists can also
prescribe now.
And also there are drugs that people take that can interact with each other.
Clearly these may be drugs prescribed by your doctor and he may not have been
aware for the interaction or that he may have decided to use them anyway because
it was needed in you to treat the disease.
But sometimes patients also take drugs and one area where I just want to focus
on foot one slide or two slides is really herbal medicines.
25% of the population take herbal medicines at the moment and herbal
medicines can interact with certain drugs so I'm just going to tell you about one
patient I saw when I was doing a ward round in my accident emergency department
and it was a lady of 77 years old who came in with bleeding vomiting blood
and she had a history of reflux that is she had a hiatus hernia and she had
inflammation of her gullet and for that treatment she had been put on a drug
called Lanzoprazol which is a drug which reduces acid reflux and reduces acid
production and Domperidone which helps to reduce some of the acid reflux as well.
But
in the history it was noted that she was on all these drugs but nobody had asked her
whether she was on taking anything else.
So I went through other drugs that she was taking including drugs that she may
have been taking herself both from Holland Barrett for example.
And she was also taking St John's Wart, she was also taking Feverfew, she was
also taking Ginseng and Garlic.
Now you may think that doesn't matter, that is a perfectly harmless.
Well in fact what was happening here was a very complex interaction and I don't
want to go through the specifics of the interaction but basically St John's
Wart reduces the ability of Lanzoprazol to work properly because it increases
the breakdown Lanzoprazol in the liver and so therefore the patient wasn't
getting enough Lanzoprazol and that promoted her reflux and the reflux came back
and she then developed inflammation of the gullet.
She was also taking three drugs which affect the platelets that is Feverfew,
Ginseng and Garlic and by themselves they may not be very efficient at blocking
platelets but when you take them together they completely paralyse the platelets.
So here was a lady who was not getting enough anti reflux medication so the gullet
became inflamed and she was taking drugs or herbal medicines which were affecting
a platelets so that she started oozing from her inflamed area and started vomiting
blood and clearly some education on the part of patients on the label of these
herbal medicines as well as doctors taking appropriate histories would have been
important in trying to prevent some of these problems.
So now let me actually go to genetics itself and pharmacogenetics is one
method to improve the benefit-harm balance of the drugs we use.
So what is pharmacogenetics?
Well, pharmacogenetics is a term which was introduced in 1957 by a German
pharmacologist called Vrogel and basically he said that we vary in the way
we respond to drugs and there may be genetic differences between us which there
are and I'll come back to that in a minute which determine the fact that we can
vary in the way we respond to drugs.
So the overall definition is the study of the genetic basis for the difference
between individuals in the way we respond to drugs.
So this is the basis and goal of pharmacogenetics.
So if I just step away and try to show you the just point to certain areas on the
slide so at the moment this is what we do is treat all patients with the same
kind of drugs coming through a particular clinic for example.
Within that group of patients you may have the green individuals here who are
very good responders, some patients who develop side effects and some patients
who don't respond at all.
So what genetics will help us to do is to identify those who are in the blue
and those who are in the orange so that we can remove these non-responders
and give them something else or remove those patients who develop side effects
and give them something else.
So what we will be left with are these individuals in the green who respond
to the drug first time so that they get the right dose at the right time
at the right dose and this is the basis of personalised medicine
and the way genetics may help in the future.
And we have enormous amount of information to be able to help us try to do this
and develop the evidence base for it.
The Human Genome Project was published in 2001 and then we've had something
called the HAPMAP project and basically what this is is
a map of the genetic variation within the human population.
And so if you look at human population
irrespective of race, colour, creed, 99.9% of our human genome is exactly the same.
But 0.1% is different and 0.1% equates to about 3 million different
letters if you like within your human genome which are different
between each of us and that obviously produces a lot of variability
and that's responsible for determining a height for example, determining
eye colour, determining its hair colour or how quickly your hair goes grey.
And this kind of variability is also seen on Liverpool despite what you may
see on Anfield on a Saturday afternoon and what the internet says.
So what are the sources of variability within the body which can affect the way
people respond to drugs, differently respond to drugs?
Well you can divide them into two different categories.
One which is called pharmacokinetic and one which is called pharmacodynamic.
So what is pharmacokinetics?
Well pharmacokinetic is what the body does to the drug.
So when you take a drug, the drug goes into your stomach, into your small intestine
and it is absorbed from there, it is transported in the blood to the area
that it needs to work on and then it is got rid of by the liver and that's where
the drug is usually broken down and then the drug breakdown products or the drug
itself is excreted from the body via the kidneys in the urine.
And this, the whole process of this is called pharmacokinetics and pharmacokinetics
varies between different individuals and that can be genetic or it can be
due to environmental factors such as other drugs being taken as I showed you earlier.
Then the second aspect is pharmacodynamic.
That is what the drug does to the body
and the drug will interact with various different molecules in the cell.
It could be a receptor, it could be an enzyme in the cell, it could be iron
channel within the cell.
These are all big proteins in the cell which can also vary between different
individuals and that also leads to some of the issues in terms of variability in
the way we respond to drugs.
So you can imagine that there are many different pharmacokinetic processes
and there are a huge number and some of them have been discovered of pharmacodynamic
processes and trying to piece that together is trying to piece a million word,
a million piece jigsaw puzzle if you like and it will take time to piece
all those pieces together.
So let me give you an example where it has worked wonderfully well.
This is with a drug called abacavir.
Abacavir is a drug which is used in HIV disease.
It is a very effective drug.
It works in combination with other drugs and reduces the viral loads so that you
can't actually detect the virus in the patient's bloodstream.
So this drug unfortunately causes a serious adverse reaction which is
characterised by a skin rash, fever, breathlessness sometimes affecting your
stomach and in patients who are re-challenged with the drug it can cause
death and this occurs in about five percent of the population who take it.
Now work done by a group in Australia, a group in the North America and ourselves
in Liverpool and Manchester were able to show a very strong association with one
particular gene which is on chromosome 6 in the human body and the gene name is there.
You don't particularly need to remember it but that's a gene name that we found
was important in predisposing to this abacavir hypersensitivity reaction.
What we were also able to show and this is important for the NHS because the NHS
doesn't have unlimited resources is we were able to show that if we were to put
this test into the HIV clinics and tested everybody who was going to go into
abacavir this would reduce the incidence of hypersensitivity and would save the
NHS money and this was taken up by the NHS, it was taken up by NHS managers and
since the end of 2005 every HIV clinic in this country has been doing this test
whenever a patient is about to go on abacavir and what has been the effect of
this? Has it been beneficial? Well it certainly has been if you look at this data
from a clinic in Brighton so before this B571 testing was introduced the
frequency of hypersensitivity was six and a half percent which is the kind of
frequency you see throughout the world for this before this test was introduced.
Since 2005 2006 I think Brighton introduced it the frequency of hypersensitivity has
gone down to zero so this is a genetic test which is working in practice.
It was found in the laboratory in 2002 it was in clinical practice being used
in HIV clinics in 2006 four years which is not very long within medical research
to be able to get that patient benefit and this is now been shown all over the
world in Australia there's a reduction in incidence of hypersensitivity with this
test in France same thing in the United States data as well now coming through
and in another clinic in London in Chelsea which is also shown this reduction
and that's a very very important advance through pharmacogenetics.
So we now I'm just telling you exactly what we're going to do at the moment
really to look at another drug which is very important which is Warfarin.
Warfarin is a hugely important drug in terms of the fact that it is so widely used
at least 600,000 people in the UK are on Warfarin and it's used for
thromboembolism, DVTs that you heard of or it is used to prevent strokes
from patient people who have irregular heart rhythms and there is a huge
variability in the dose requirements for Warfarin which we can't predict at the
moment and what unfortunately happens in some patients is that they get bleeds
as in this 82 year old lady who is on Warfarin for six weeks who developed
this bleed in her leg in a calf muscle and had to spend a couple of weeks
in hospital trying to recover from this and learn to walk again and what we want
to do is to prevent this. Now a lot of work has been going on throughout the UK
as well as throughout the world in trying to improve how we use Warfarin
and work done here, funded by the Department of Health, funded by the NHS
if you like, has shown that there are two main genes and again they are listed
over here, again you don't need to know what there are particularly but one is
in the vitamin K pathway and one is a P450 enzyme, one of the enzymes which
breaks down Warfarin in the liver and those are partly responsible for some
of the variability we see in Warfarin but clearly environmental factors
are important, again gums back to my point before, you can't treat genetics
by itself, you have to look at genetic and environmental factors together
and the interaction between the two, nature and nurture and age and body weight
also affect how much Warfarin is required by the patient and utilizing these
four factors we can account for 55% of the variability in requirement for
Warfarin in terms of daily doses and so hopefully we can try to improve the way
we use Warfarin and so what we're doing at the moment and we've just been funded
by the European community to do a trial on this and the trial is about to start
and it is going to be held in seven centres in Europe with 2,700 patients.
The 900 patients with Warfarin will be from UK and from Sweden but there are
other kinds of anticoagulants which are used in other parts of Europe and these
are listed on the slide and these will be tested at the same time so we have
three trials if you like going on side by side in different countries in Europe
and what we're doing here is using a point of care test.
What this means is that we have this black box which is in every clinic.
We will be able to take a single blood spot from your finger, put this into
the machine and it will be able to tell us your genetics for these three genes,
three particular variants in 60 minutes and this test is hopefully going to cost
less than £10 to be able to do this but the cost hasn't been evaluated yet
but hopefully it will be less than that and that's what we're aiming for.
The important point here is that we're testing whether pharmacogenetics improves
how we can use Warfarin, improves the safety of Warfarin but it also tests
whether we can use these kind of technologies within the clinical situation
so that we're not harming patients by using technologies which haven't been
adequately tested and that's very important and this is a very important trial
which is a similar trial is also going on in the United States due to start
again early next year and hopefully the lessons from this will then be
incorporated into where the way we use Warfarin within the NHS.
So whatever we're trying to do is we're trying to close the loop.
There's no point you just finding a genetic variation within a human being
because you now then need to show that if you then prescribe that drug
you need to show that genetic variation and utilising that genetic variation
in the way you prescribe the drug actually makes a benefit to the patient.
So in the kind of work that we're doing is that we're trying to close the loop
we're going from, sorry, wrong one, we're trying to find this variation
and then really go round the circle and show that it is having a positive clinic outcome.
It is maximising benefits of the drugs and minimising harms of the drugs
and so what I've tried to do is that we require evidence to do this.
Evidence, evidence, evidence all the time and this does take a long time
to be able to produce the evidence and without the evidence it is,
it may be that some genetic test might actually harm the patients rather than benefit the patients
and it is the work that we do and the work that is going on throughout this country
is really to build up the evidence space so that we can introduce the genetic tests
into the NHS in an evidence-based fashion which is there to maximise benefit
and not harm the patients.
And this is seen in some of the issues which are already out there
and if you look at Cytochrom P452D6 some of you may be aware of this.
This is an enzyme which is absent in at least 8% of the UK population
and it is involved in the breakdown of antidepressants
and I know that Milly is very interested in this particular enzyme
and it said that you could tie patients for this Cytochrom P452D6
before you put them on antidepressants.
However, the evidence just isn't there, I'm afraid at the moment
and this evaluation was done by a very respected organisation in the United States,
the Association for Health Research Quality,
and they went through all the data which is out there in the literature
and what they came up with was a conclusion
that we just don't have the evidence at the moment
to be able to say whether it helps or whether it hinders.
And so I'm not saying that it doesn't help at all
but what we need to do is to do the right studies
so we can provide the evidence space so that we can introduce it in the NHS
in the best way possible so that patients benefit.
And the problem that we have with genetic tests at the moment
is that there isn't very much evidence for many genetic tests
which are being offered to the public
and there is a potential that may harm the public.
And this is from science which is a very respected journal
and from earlier this year.
And what they said was that today there is no mechanism
to ensure that genetic tests are supported by adequate evidence
before they're marketed or that any marketing claims that they make
are truthful and not misleading.
Misleading claims about tests may lead healthcare providers
and patients to make inappropriate decisions about whether to test
or how to interpret test results.
And that ratio I showed you that CSO benefits harm
and may be harmed by using genetic tests inappropriately
and we're desperately trying to make sure that that doesn't happen
in terms of the way we're trying to develop the evidence space.
So just to conclude, pharmacogenetic I think represents a powerful tool
with which we can improve the benefit harm balance associated with the drugs
that we use in the NHS today.
It is however only one of the many different methods
that need to be further developed and tested
to be able to improve patient care.
With any intervention irrespective of whether it's genetics,
irrespective of whether it's clinical, it is important that there is a good evidence space
to ensure that you do not inadvertently harm your patient.
And this is what exactly we're working towards.
Thank you for your attention.
I'm actually pushing for a genotyping test to be available to every patient
before they are prescribed psychiatric drugs
no matter what drugs they are being prescribed.
And I'm encouraging the nice guidelines to look into
the script for genotyping.
And I understood that from Louis Appleby
that research was being done at the university which you represent.
Am I correct?
We have been doing an evaluation of cytogram P452D6
with antipsychotics, not antidepressants.
Antipsychotics?
And this is via NICE.
So the work is going on at the moment
and it is going to go to NICE very soon.
So I can't, I don't have the exact, the final data at the moment.
But what we have done and we've worked on this
for at least 18 months, really literature searching,
looking through every database we have, every,
we try to contact researchers throughout the world
to be able to get their data and then put it together to see
whether there is a true benefit of 2D6 testing before you go on antipsychotics.
And as I said, what we want to do is to make sure that the evidence base is there
that it actually helps the patient and at the moment
all I can go in is by the evidence that's out there in the literature.
Okay, well I feel quite deceived in so much that
the pharmacist in with the caretress never told me
when my son was prescribed psychotic drugs
that there was this test available
and having to pay for this test privately far more than £10,
I do assure you that my son is a poor metaboliser, the CYP2D6
and an intermediate metaboliser for the 2C19
and he has reacted very acutely and adversely to all the psychotrophic drugs.
And I just think that the genotyping test
that should be made to patients and care as awareness
that this test can be bought up front.
Interestingly, my interest in this field is due to my own experience
of being prescribed several years ago
a couple of drugs relating to psychiatric medicine
which caused adverse medical conditions
and it's more of an observation.
One of the curious things that since I've been looking at
and I would just be grateful for your thoughts
was blood grouping, something as simple as that.
I just wonder if there is any substance in the concept
that different blood groups have different blood functions, characteristics
and relating to that, it strikes me that body chemistry
when I did my clinical dissection practice many years ago
it was rather striking particularly in the limbs
how anatomical features varied enormously
and when you think about it to have a variation in gene pool
is actually quite logical because it does lead to diversity
which is helpful for survival
and in that way biochemistry, body chemistry, metabolism, endocrine function
it strikes me that it's logical that there are variations
in all sorts of features like the vitamin K drug you mentioned
the vitamin K that you mentioned I think
where bodies have variations in function
and I was just grateful for your thoughts, thank you.
So you're quite right, there is variability
and as I said there are 3 million different base pairs
of human genome which vary amongst us
and that does lead to variability in some anatomical structures
variability in your biochemistry, variability in metabolism
variability in your receptors
and so the important thing is trying to disentangle all that
and provide the evidence as to what genetic test you use
you could say that you could go and do your whole human genome
but at the moment that costs £300,000 per human genome
and we don't know how to interpret that
but in regard to the blood groups clearly blood groups
are an important genetic determinant
if you require transfusion which blood cells you should be given
and there is evidence that blood groups also determine your susceptibility
to certain diseases such as malaria and so on
but there is at the moment apart from certain drugs
which cause hemolysis which cause a breakdown of blood cells
there is no evidence that they determine response to for example psychiatric drugs etc
but clearly there are many different variants on blood cell surfaces
which may impact on how well I read blood cells work and so on
and that kind of data just isn't available at the moment.
Charles Merua, thank you for an interesting talk
you give very persuasive evidence that genetic predisposition
is going to influence response at least in a minority of people treated with drugs
but have you made any estimate is it possible to make any estimate
of the total burden of clinical atrogenesis
taking into account that personalised medicine has only just begun
we are on the receiving end of mass marketing
mass marketing techniques and there are no such refined tests
so I am looking at the other side of the coin you described
and wondered if you could estimate how great the atrogenic burden might be
from the lack of investigating of genetic factors
lack of investigation of genetic factors in determining drug response.
As you will be aware Mr Merua is that it is difficult to give an overall figure
for the whole therapeutic armamentarium that is available to the prescribing doctor
because all drugs are handled differently in the body
but for some drugs it may be 100% of the effect size
for some drugs it may be less than 5%
and what we are trying to do at the moment is try to get that kind of variability
of the estimate of the effect size within each particular drug group
and there are various ways of doing that and there is lots of work going on
all around the world to be able to do that.
It has been said in the literature that maybe at least 30% of adverse effects
to drugs could be prevented by genetics.
Now that is an estimate and may be grossly wrong
or may be under estimating or over estimating
so in terms of the whole therapeutic armamentarium that we have
but within individual drug categories it could be 100% in terms of preventing it
or it could be less than 5%.
I run a co-ordinator of a support group
and I have a son who has had difficulties.
You were talking about the evidence base that is needed
and is particularly interested in the P45
and the absence in the general population, this polymorphism difficulty.
DEFRA, Funded by Government, DEFRA Science has done many many years,
six, seven years of intensive research into how environmental factors
may or may not impact on people particularly with regard to exposure to agricultural chemicals
and again it phosphates in particular.
The results of that research have been minimised by government
when they have come out or been slow in being released
and I wondered if you are accessing some of that information.
One that came out by Nicola Cherry
was specifically about sheep farmers who do and don't react
and it was this pathway or this mechanism that they were exploring
and it found quite conclusively that there was considerable evidence
that those that were affected by the chemicals did have this limitation in their bodies.
Now residents and people in rural areas like myself,
we are also being exposed in the same way as sheep farmers
and my son was evaluated by the London School of Hygiene and Tropical Medicine
Tony Fletcher's Shape study which was looking at sheep farmers
and those that have been exposed
and his score was far in excess of people who had an acute effect.
None of this was taken into account when he was given an SSRI
not for mental health problems but physical health problems by the GP.
No history was taken and no evaluation whatsoever was done of the impact of this drug
being given to a 16-year-old in these difficult circumstances
who already had diagnosis of a severe form of a chronic long-term health condition.
So with regard to organophosphate poisoning and organophosphate exposure
we are not ourselves doing any work on that
but I know that there is a lot of work going on throughout the UK
and I know that of DEFRA's work.
Clearly in terms of the relationship with the SSRI that your son was given
it is difficult for me to comment on individual cases and so on
and I'm happy to discuss with you at Coffey our possible links and so on
but organophosphates obviously are very complicated chemicals
which undergo different pathways.
There may be some overlapping pathways
and whether that overlap in pathways has any relevance or has been investigated
is unclear at the moment and what that overlap is
and I think there is more work that needs to be done in that kind of area.
I'm really pleased that you're doing research on morphering
which is pretty straightforward with the two polymorphisms.
I think psychotropic drugs are a bit more problematical
because most of them go through 2D6 and there's the 2C19 and the 2C9
but I think it could be dangerous as you said
if you get a negative for any polymorphism on those CYP450s.
Is there a genotyping test for example the serotonin transporter gene
and how good would the result on that be, how useful would that be?
I haven't shown you all the data on morphering
there are 29 genes in fact involved in morphering
so I just showed you two and you're quite right with antidepressants
there are the P450s, 2C9, 2C19, 3A4, 3A5 etc. 2D6
but there are also the pharmacodynamic genes
the 580 transporter, the 580 receptors etc.
which are all very important. The problem is and depression
is an important area to study with regard to genetics
and I quite agree that there might be some genetic factors
but I just don't have evidence based to tell you confidently
that those genetic factors have been found
and so what we need and there needs to be funding for this
is to do the studies so that we can look at 2D6, 2C19,
we can look at the 580 transporter, we can look at the 580 receptor genes
and put them all together and look at the interaction between them
so that we can develop those kind of methods
so that we can treat patients with depression
with the appropriate drug at the right dose
so that they get the benefit rather than the harms.
So that is valuable for me to come here and listen to families,
listen to patients, relatives, patients etc.
telling me that they have these side effects
so that I can then develop a picture and say
well we do need funding for this, we do need to take this further forward
so that we can develop the appropriate test to help patients out there.
The main question I had is when you have an adverse drug reaction
which causes damage to the cytochrome liver pathways
are there any mechanism by which this can be addressed?
Damage is the cytochrome P450 pathway.
Cytochrome pathways, for instance for cytochrome P450?
Right, so if you have an, you can either have an absence cytochrome P450
or a deficient cytochrome P450, a normal level of cytochrome P450
or higher level of cytochrome P450.
Sometimes drugs do interact with cytochrome P450
and can reduce the activity of it, but once you get rid of that drug
the cytochrome P450 value should come back to what it was at baseline.
So there's nothing I know of, a drug that we use
that can completely get rid of your cytochrome P450 forever
because the liver is continuously regenerating cytochrome P450
so it should come back to what it was within two weeks of taking you off the drug.
Yes, but quite often it doesn't and as a result
quite a few people who've had adverse reactions to pharmaceutical drugs
find that they are no longer able to metabolise drugs
and although this is not understood
but I would like to know if there are any research being done concerning this.
I think your question is why do patients,
I'm sorry I'm having difficulty hearing,
is why do patients who've had a side effect of the drug
can no longer metabolise drugs
but it may be that they couldn't metabolise the drugs in the first place
which caused the side effect in the first place
so the drug hasn't changed anything
but the person couldn't metabolise the drug in the first place.
So for example if you look at cytochrome P450 2C9
which is involved in warfaring
one in 500 of the population
have a deficiency of the cytochrome P450 2C9
such that they only have 5% of the metabolising capability.
Now that means that they were born with that
that the warfaring hasn't caused that.
So I don't know of any drug which actually breaks down your P450
and then you don't regenerate it back.
So any inhibition of P450 is transient while taking the drug.
Once you stop the drug your P450 should come back to what it was at baseline.
If you were born without that particular P450
they would come back to what it was at the time you were born really.
And how reliable are genomic testing?
How reliable is genomic testing?
Well it depends which P450 you're talking about
so if you look at the cytochrome P450 2D6
which is I guess one of the most interesting ones from your perspective
is that there are 85 different kinds of variations within that.
Most tests will not look at all those 85 variations
they will look at 4 which accounts for about 95% of the variation within the P450.
So they're not 100% reliable in that way
and that again is the problem that I have
is that what we don't want to do is to introduce testing
that will cause harm to some patients
because it may give a false reassurance to the patient as well as to the doctor.
And so all we need are tests which actually provide as much resonance as possible
to make sure that we're not harming patients and that is my biggest concern.
Thank you.
