●Introduction: ‘personalized medicine’ 79
●Genetic influences on drug metabolism 79
●Genetic influences on drug disposition 82●Genetic influences on drug action 82
●Inherited diseases that predispose to drug toxicity 83CHAPTER 14
PHARMACOGENETICS
INTRODUCTION: ‘PERSONALIZED MEDICINE’
Variability in drug response between individuals is due to genetic
and environmental effects on drug absorption, distribution,
metabolism or excretion (pharmacokinetics) and on target protein
(receptor) or downstream protein signalling (pharmacodynam-
ics). Several idiosyncratic adverse drug reactions (ADRs) have
been explained in terms of genetically determined variation in the
activity of enzymes involved in metabolism, or of other proteins
(e.g. variants of haemoglobin and haemolysis). The study of vari-
ation in drug responses under hereditary control is known as
pharmacogenetics. Mutation results in a change in the nucleotide
sequence of DNA. Single nucleotide polymorphisms (SNPs) are
very common. They may change the function or level of expres-
sion of the corresponding protein. (Not all single nucleotide vari-
ations change the coded protein because the genetic code is
‘redundant’ – i.e. more than one triplet of nucleotides codes for
each amino acid – so a change in one nucleotide does not always
change the amino acid coded by the triplet, leaving the structure
of the coded protein unaltered.) Balanced polymorphisms, when
a substantial fraction of a population differs from the remainder
in such a way over many generations, results when heterozygotes
experience some selective advantage. Tables 14.1 and 14.2 detail
examples of genetic influences on drug metabolism and response.
It is hoped that by defining an individual’s DNA sequence from a
blood sample, physicians will be able to select a drug that will be
effective without adverse effects. This much-hyped ‘personalized
medicine’ has one widely used clinical application currently, that
of genotyping the enzyme thiopurine methyl-transferase (which
inactivates6-mercaptopurine(6-MP)) to guide dosing 6-MPin
children with acute lymphocytic leukaemia, but could revolu-
tionize therapeutics in the future.
Throughout this chapter, italics are used for the gene and
plain text for the protein product of the gene.
GENETIC INFLUENCES ON DRUG
METABOLISMAbnormal sensitivity to a drug may be the result of a
genetic variation of the enzymes involved in its metabolism.
Inheritance may be autosomal recessive and such disorders
are rare, although they are important because they may have
severe consequences. However, there are also dominant pat-
terns of inheritance that lead to much more common varia-
tions within the population. Balanced polymorphisms of drug
metabolizing enzymes are common. Different ethnic popula-
tions often have a different prevalence of the various enzyme
polymorphisms.PHASE I DRUG METABOLISMCYP2D6
TheCYP2D6gene is found on chromosome 22 and over 50
polymorphic variants have been defined in humans. The func-
tion of this enzyme (e.g. 4-hydroxylation of debrisoquine, an
adrenergic neurone-blocking drug previously used to treat
hypertension but no longer used clinically) is deficient in about
7–10% of the UK population (Table 14.1). Hydroxylation poly-
morphisms in CYP2D6explain an increased susceptibility to
several ADRs:- nortriptyline– headache and confusion (in poor
metabolizers); - codeine– weak (or non-existent) analgesia in poor
metabolizers (poor metabolizers convert little of it to
morphine); - phenformin– excessive incidence of lactic acidosis (in
poor metabolizers).
Several drugs (including other opioids, e.g. pethidine,mor-
phineanddextromethorphan; beta-blockers, e.g. metoprolol,
propranolol; SSRIs, e.g. fluoxetine; antipsychotics, e.g.
haloperidol) are metabolized by CYP2D6. The many geno-
typic variants yield four main phenotypes of CYP2D6 – poor
metabolizers (PM) (7–10% of a Caucasian population), inter-
mediate (IM) and extensive metabolizers (EM) (85–90% of
Caucasians) and ultra-rapid metabolizers (UM) (1–2% of
Caucasians, but up to 30% in Egyptians) due to possession of
multiple copies of the CYP2D6gene. UM patients require
higher doses of CYP2D6 drug substrates for efficacy.