PERSONALISED MEDICINES SYMPOSIUM
Warwick Medical School
Medical Teaching Centre, University of Warwick
Wednesday 5th July 2006
Magnus Ingelman-Sundberg
Section of Pharmacogenetics
Department of Physiology and Pharmacology
Karolinska Institutet
SE 171 77 Stockholm, Sweden
PHARMACOGENETICS AND DRUG RESPONSE
Drug treatment is in many cases ineffective. Non responders and patients suffering
from adverse drug reactions is estimated to cost the US society 100 billion USD and
over 100,000 deaths per year. Many drug transporters are polymorphic. In addition,
the majority of phase I and phase II dependent drug metabolism is carried out by
polymorphic enzymes which can cause abolished, quantitatively or qualitatively
altered or enhanced drug metabolism. Stable duplication, multiduplication or
amplification of active genes, most likely in response to dietary components that have
resulted in a selection of alleles with multiple non-inducible genes, has been
described. Several examples exist where subjects carrying certain alleles suffer from
a lack of drug efficacy due to ultrarapid metabolism caused by multiple genes or by
induction of gene expression, or, alternatively, adverse effects from the drug
treatment due to the presence of defective alleles. The evolutionary aspect of the
genetic polymorphism in these genes includes genetic drift but also selection because
of environmental stress. We propose that an alkaloid resistance has developed in
North-East Africa in response to a dietary selection of alleles containing multiple
CYP2D6 gene copies. We have recently identified also an ultrarapid allele of CYP2C19
and novel variants of CYP2B6 and CYP3A7. The information about the role of
polymorphic drug transporters and drug receptors for efficiency of drug therapy is
scarcer, although promising examples are seen in drug treatment of e.g. asthma and
epilepsy. It is likely that predictive genotyping in the future will be of benefit in 20-30
% of drug treatment and thereby allows for prevention of causalities as a cause of
ADRs and thus improves the health for a significant fraction of the patients. Recently
several important clinical examples have been given. For studies of associations
between the occurrence of genetic variants and pharmacokinetics it is of severe
importance to consider the true haplotype, focus on functionally relevant mutations,
identify the true phenotype, recruit relevant patient groups, analyse a cohort of a size
large enough yielding enough power and to reproduce the findings in an independent
set of samples. In the lecture examples will be given where pharmacogenetics has
been dealt with in an appropriate and less appropriate manner for prediction and
analyses of drug pharmacokinetics and suggestions for correct study designs will be
provided.