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ТОКСИЧНІСТЬ ТА
БЕЗПЕЧНІСТЬ
ЛІКАРСЬКИХ ЗАСОБІВ
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Токсичність як проблема невдач у
клінічних дослідженнях
Only about 1 in 9 compounds going into Phase 1 clinical
trials will become marketed medicines.
We have improved our ability to predict pharmacokinetics
in man since 1991. In 2000, bad toxicology was the main
reason for failures.
1991 2000
Reasons for failure of medicines in clinical trials
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Токсичність як проблема невдач у
клінічних дослідженнях
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Токсичність на основі механізму дії
Утворення токсичних метаболітів
Активація інших мішеней
Взаємодія з іншими речовинами
Ідіосинкратична токсичність
Види токсичності
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Caused when activation of the target causes unwanted
effects as well as the desired therapeutic effect.
Balance of good/bad effects.
Usually not predictable from in vitro tests, but can
sometimes be predicted from animal models.
A big potential problem with drugs designed for
completely novel targets, rather than new drugs for a
known mechanism.
Токсичність на основі механізму дії
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ß-agonists (e.g. salbutamol) are used to control asthma by
causing activation of the ß2 receptors in the lung. This
causes the airways to dilate.
These compounds are taken by inhalation, so most of the
drug stays in the lung.
Приклад: бета-агоністи
salbutamol
If the patient takes too much medicine,
the levels in the systemic circulation rise
and can now affect the ß2 receptors in
the heart causing palpitations.
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We don’t want chemically reactive medicines!
What functional groups might we want to avoid?
e.g.
These are all electrophiles, which means that they
can covalently bind to nucleophiles in the body, e.g.
in proteins and DNA which lead to toxic effects.
Most common effects are hepatotoxicity (liver) &
genotoxicity (DNA).
But don’t forget that in the body, chemicals are
metabolised so we need to consider the fate of our
new medicine – will any of the metabolites be
chemically reactive?
Утворення токсичних метаболітів
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Небажані функціональні групи
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Nitro
Acylating agents
Isocyanates
Mono-substituted
furans and
thiophenes
Alkylsuphohonate
esters
Anilines
Electophilic
aromatics
Terminal
acetylenes
Electrophilic esters
Michael acceptors
Aziridines
Epoxides
Azo
Masked anilines
Disulphides
Alkylhalides
Chloroamines
Certain
phenols
Hydrazines
Небажані функціональні групи
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Приклад: парацетамол
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Paracetamol would never be
acceptable to today’s drug
regulatory bodies
Sometimes known as ‘off-target toxicity’.
Screen against other systems – similar targets will be
done early on in the project. Before nomination to
preclinical studies, the compound will be tested in many
other assays to look for activity.
Potency (and therefore dose) is important as we are
looking for a safety margin, i.e. the absolute potency at
another receptor is less important than how much less
than the potency at the primary receptor it is.
Remember! If pIC50 (A) = 7.0 and pIC50 (B) = 6.0, the
margin is 10x. But if pIC50 (A) = 9.0, the margin is 1000x.
Активація інших мішеней
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hERG = ‘human ether-a-go-go
related gene’ (ген
специфических калиевых
каналов сердца человека)
hERG
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“Ether a-go-go”
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hERG = ‘human ether-a-go-go
related gene’ (ген
специфических калиевых
каналов сердца человека)
Potassium channel
Activation causes prolongation
of electrical impulses regulating
heart beat
Can lead to fatal arrhythmias
hERG
Q
P
S
R
T
Q
P
S
R
T
Normal heart beat Activation of hERG
‘T’ wave is delayed
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Lots of marketed drugs bind to it, with apparently diverse
structures.
e.g.
grepafloxacin (antibiotic)
hERG
terfenadine (antihistamine)
astemizole
(antihistamine)
sertindole (neuroleptic)
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Lipophilic base, usually a tertiary amine
X = any 2-5 atom chain
Фармакофор hERG
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hERG IC50= 5800nM
calculated pKa = 8.6
calculated logD = 0.3
hERG IC50= >50,000nM
calculated pKa = 8.5
calculated logD = -3.3
Приклад: інгібітори фарнезилтрансферази
Changing the lipophilic aromatic ring to a polar one
reduces hERG activity by >10x.
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It’s complicated enough to look at the pharmacokinetics,
toxicology etc of one medicine at a time, but many
patients take several medicines, which can interact……
What might cause this?
One substance can affect the metabolism of another.
This is why many medicines have a warning on them to
say that the patient shouldn’t drink alcohol whilst taking
the medication, because alcohol metabolism can affect
drug metabolism.
Взаємодія л/з (DDIs)
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Main metabolic pathway – CYP action, so compounds
which inhibit and induce CYPs have the potential to
interact with many other drugs.
Приклад: MAOIs and the ‘cheese effect’
Monoamine oxidase inhibitors (MAOIs) have antidepressant
activity.
Depressed individuals often have decreased levels of amines
such as noradrenaline, serotonin and dopamine in the brain.
MAOIs increases these levels by reducing oxidation of the
amines.
However, they are not the drug of choice as they are
sometimes associated with cardiovascular side effects.
noradrenaline (R = OH)
dopamine ( R = H)
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Side effects caused when patient has eaten food which
contains high levels of tyramine, e.g. cheese, wine, beer.
Ingested tyramine causes the release of noradrenaline
(NA), which would normally be metabolised by MAOs.
But because these enzymes have been inhibited, the NA
levels rise. As NA is a vasoconstrictor, the blood pressure
rises uncontrollably, which can trigger a cardiovascular
event.
tyramine (R = H)
serotonin (R = OH)
noradrenaline
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Приклад: MAOIs and the ‘cheese effect’
‘Idiosyncratic toxicity’ is something of a catch-all term to
include other toxic effects that we don’t currently
understand.
Note that increased potency reduces the possibility of this.
It is desirable to have two or more compounds in
development which are structurally different – this reduces
the possibility of both being hit by idiosyncratic toxicity
problems.
It’s a continuous challenge to understand the causes of
idiosyncratic toxicity therefore to be able to avoid them at
an early stage.
Ідіосинкратична токсичність
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Доклінічна токсикологія
Before human studies, it is necessary to demonstrate
safety in vitro and in vivo.
These assumptions are broadly true, but despite this, we
cannot be certain that a chemical will show no toxic effects
in humans.
We assume that
in vitro assays predict in vivo effects
the effects of chemicals in laboratory animals apply to
humans
the use of high doses in animals is valid for predicting
possible toxicity in humans.
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‘Ames’ test to detect mutagenicity
Use a genetically modified bacterium which cannot
grow in the absence of histidine.
Expose bacteria to chemical.
If the chemical can cause mutations, the genetic
modification can be reversed and the bacteria will grow.
Can also be carried out in the presence of liver
enzymes to look for mutagenic metabolites.
Тести на утворення токсичних
метаболітів
Test for the presence of reactive groups
Look for binding to proteins or
glutathione - detect by mass
spectroscopy
glutathione
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Тест на hERG-безпечність
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Тести на взаємодію л/з: CYP активація
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