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Clinical Pharmacy in the Genomic Era
Folklore ascribes the birth of pharmacogenetics to
Pythagoras (3), the 6th to 5th century BC Greek
philosopher, mathematician, and mystic because he
forbade the eating of broad beans which causes haemolysis
in some susceptible subjects. This causal association which
was subsequently linked to an inborn deficiency in
glucose-6-phosphate dehydrogenase (G6PD) established
him as the first pharmacogeneticist in the eyes of many.
Over two millennia later, the perceptive Charles
Darwin recognised that adaptation contributed to wide
variability in people’s responses to toxins and that through
natural selection different groups could develop different
levels of resistance to toxins at the population level.
However, Darwin found it difficult to provide a
mechanism for inheritance. He theorized that when
children are conceived, they inherit a blend of their
parents’ traits. Black and white would yield in-between
shades of grey. He was unable to explain why blending did
not continue until there was no more white or black.
The theory of numbers developed by Pythagoras and
his followers would help resolve Darwin’s dilemma. The
sciences of numbers, they said, could be divided into two
broad classes: numbers to describe how many (discrete
mathematics) and numbers to describe how much
(continuous mathematics). Pythagoras used continuous
mathematics to describe music, and thereby also laid the
foundation of harmonics.
It was with the use of discrete mathematics that Gregor
Mendel generated the data for his Laws of Inheritance with
his studies of the genetics of peas.
The discovery of monogenic diseases
Darwin was not aware of Mendel’s work. In fact, even
Mendel’s contemporaries working on plant breeding did
not immediately recognise the significance of Mendel’s
work. However, one biologist, William Bateson, working
in Cambridge, soon recognised the wider significance of
Mendel’s discoveries.
Archibald Garrod, an astute London clinician inferred
that alkaptouria, a strange and rare condition characterised
by the deep browning, and eventual blackening of urine,
when exposed to air, was due to a metabolic abnormality
that led to the accumulation of homogentisic acid (4).
When he discussed this abnormality, which he established
was an ‘inborn error of metabolism,’ with Bateson, the
latter worked out that it was indeed a hereditary
abnormality, and even more importantly that its
inheritance followed Mendel’s Law of segregation. Much
of the genetics terminology that we use today owe their
origins to Bateson (5). Over 6000 single-gene disorders are
known and many, once fatal, are now manageable with
recombinant replacement enzymes.
Although he was no pharmacogeneticist during his
lifetime, with his development of the mathematical
concepts that allowed Mendel’s to develop his theory,
Pythagoras has earned his place as one. What is discrete
and what is continuous is of course often just an illusion as including the following four.
mathematicians studying wave mechanics have shown us.
@Real Academia Nacional de Farmacia. Spain
Werner Heisenberg (6) showed us that there was much
uncertainty in the observation of physical phenomena. We
have come to realise that in pharmacogenetics, discrete
units of inheritance can produce apparent Darwinian
‘blending’ when many genes contribute to a trait of
interest, such as a drug response. Such traits are described
as polygenic. Sometimes matters become more
complicated and the traits are also affected by
environmental influences as Darwin first surmised. Such
traits are referred to as complex polygenic and
multifactorial. Skin colour is an example but so are many
drug responses. All pharmacists are of course aware of the
potential clinical impact of drug-drug and drug-diet
interactions.
Much of the early pharmacogenetics work focussed on
adverse effects of drugs (7). These included excessive
prolongation of the action of suxamethonium (8), and the
haemolysis induced by antimalarial drugs, notably
primaquine (9,10). The latter case brought us back to
Pythagoras as the adverse effect was associated once again
with G6PD dehydrogenase (11). Such adverse effects led
Motulsky to observe:
‘In discussions of drug idiosyncrasy, careful distinction
should be made between toxic reactions caused by
immunologic mechanisms (drug allergy) and abnormal
reaction caused by exaggeration or diminution of the usual
effect of a given dose. Although some progress has been
made in the study of mechanisms of drug allergy, little was
known until recently about the pathogenesis of
hypersusceptibility reactions and hyposusceptibility
reactions. Data are available now which suggest that
reactions of this type may be caused by otherwise
innocuous genetic traits or enzyme deficiencies’ (12).
The genetic basis of several hypersensitivity reactions,
previously referred to as idiosyncratic, is now well
established (13,14).
PHARMACOKINETICS AND PHARMACODY-
NAMICS
The discovery of the importance of the cytochrome
P450 enzymes in the biotransformation of drugs, led to an
explosion of studies on the impact of variants of those
enzymes on drug action. Those studies coincided with the
development of analytical and mathematical methods for
probing the disposition of drugs in the body; a field
defined by the terms pharmacokinetics and bioavailability.
Many members of the cytochrome P450 enzyme
superfamily have been identified. Although there was
much hope that identification of dysfunctional variants
would help us to personalise therapy, in practice the value
of such insights has been limited for many reasons,
Firstly, our body, like the great city of Madrid or
Barcelona, is complex; much more complex. There are
many roads leading to and out of it. When one road is
blocked, there is usually another road that one can use. So,
when one metabolic pathway is blocked, the body uses
another pathway to get rid of the drugs it receives.
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