Why do effective drugs sometimes have serious secondary effects?
Because each individual metabolises them differently. By coordinating
European research under the COST programme (coordinated action in
the field of science and technology) it has been possible to make
considerable progress in our knowledge of variations in the human
enzyme systems responsible for metabolism. Through this work, the
pharmaceuticals industry is now in a position to devise new and much
drugs that can be designed from the start
to avoid the secondary effects that vary from one individual
We are all different where drugs are concerned.
Some of these drugs are being withdrawn from sale despite having been
on the market for years. Deemed to pose no danger, they have been
found to cause serious secondary effects for some people that only
become apparent after a very long period of use. Why is this? At the
end of the 1970s various scientific reports gave rise to suspicions
that the enzymes responsible for the assimilation of drugs vary from
one person to another.
Greater knowledge in this area would make it possible to take account
of this variation when developing new drugs. Under the COST B1 action,
a research project involving 15 European countries - the complexity
of the problem being such as to require cooperation on this scale
- will help us to achieve a better understanding of such phenomena
and to take more effective action in preventing them.
Variations on a theme
For a dozen years or so, work has focused on the P450s, a particularly
important family of enzymes responsible for the metabolism of drugs.
There are nearly 40 different P450s in the human body, about half
of which control reactions involving substances which have remained
the same throughout our evolution - so much so that we all possess
virtually identical enzymes. It is probable that the other half
have evolved in such a way as to metabolise substances which our
bodies no longer secrete, and this is the category of enzymes that
interact with numerous drugs.
With the passage of time, these enzymes - now deprived of specific
functions - have undergone modifications through genetic mutations
in their DNA. Today 10% of the population possesses variants of
some of these enzymes, and these are the people who may encounter
serious problems when given a drug which is normally innocuous.
During the first four years of the research, considerable progress
was made in identifying variations in the different enzyme systems.
"Standardisation of the techniques employed in the classification
of the different human variants and in the study of the enzymes
concerned has marked a decisive stage," explains Alan Boobis, the
UK delegate on the COST B1 Management Committee. "Harmonisation
of our efforts and methods was imperative, if we were to avoid unnecessary
duplication in our work, while at the same time guaranteeing the
complementarity of our findings."
The danger of
interaction On the basis of these particularly positive results,
the action was extended twice, once in 1991 and again in 1995. The
work was broadened to take in basic research covering mathematical
approaches aimed at defining variability in the consumption of drugs
among European populations. Different groups, working in parallel,
have focused their research on specific aspects: interactions between
drugs or with other substances such as those found in cigarette
smoke, alcohol and chemical compounds in convenience foods; behaviour
of drugs in persons affected by renal insufficiency or heart disease;
reasons why the effects of drugs vary from one individual to another.
The scientists observed, for instance, that the simultaneous administration
of terfenadine, a common antihistamine for the treatment of hay
fever, along with other drugs (notably certain anti-fungal agents
and the antibiotic erythromycin) could lead to very serious, even
lethal, heart disorders in certain patients. They also came up with
an explanation of the working of the mechanisms likely to lead this
kind of accident.
The interaction (very rare but highly
dangerous) of terfenadine with certain other drugs can now
be avoided. This antihistamine is currently used in the treatment
of hay fever.
And what about the
pharmaceuticals industry? The project has had a significant impact
on pharmacology and on the development of new drugs. Twenty years
ago, before being administered to humans, a product was tested on
animals as thoroughly as possible, but often complications were
detected only after its introduction in the treatment of patients.
Nowadays, drugs are devised from the outset in such a way as to
avoid conflicts with enzyme variants. New drugs are tested not only
in vitro but also using complex computer modelling techniques, in
an attempt to eliminate any risk of unexpected secondary effects,
even among that part of the population considered to be "at risk".
Possible interactions between drugs can be described during the
design of the new products. Doctors are now much better informed
of the variations likely to occur from one patient to the next and
of the probable interactions with, for example, alcohol or coffee.
It is already possible to predict which subgroup of the population
is at risk of reacting unfavourably to a given drug by virtue of
its state of health.
In the near future it will be possible to carry out routine examinations
to detect unusual forms of enzymes affecting the metabolism of drugs;
it will be sufficient to analyse the DNA contained in a small cell
sample (from blood or cheek tissue) and to compare it with the data
base compiled mainly as a result of the COST B1 action. Using computer
models, it will be possible to simulate with some accuracy what
would happen if a given individual were to take a particular new
drug - thereby reducing the frequency of secondary effects and of
other potentially lethal reactions.
"Because of the large number of countries involved, this project
has had a considerable impact on the pharmaceuticals industry throughout
Europe," Alan Boobis points out. "Almost all the major companies
working on the development of drugs are using our discoveries as
a model. Prior to the COST B1 action, the United States was unquestionably
ahead in most areas relating to drug metabolism research. Now, Europe
has assumed the role of leading player in numerous key areas."