Pharmacogenetic biomarkers as tools for improved drug therapy; emphasis on the cytochrome P450 system

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Abstract

Important interindividual differences in drug pharmacokinetics cause absence of drug response or adverse drug reactions in significant fractions of the populations. The identification of the major enzymes participating, and the elucidation of the genetic basis for this variation in particular among cytochromes P450, provide tools for a personalized medicine treatment, which can make drug therapy much more effective at a lower cost. Much of the pioneering work linking drug metabolizing phenotype to genetic polymorphism among the P450 enzymes has been carried out at Karolinska Institutet. In this review we give a background and description of this work as well as the important implications for future medicine.

Introduction

Drug treatment is often inefficient. Only 30–60% of patients respond properly to treatment with antidepressants, beta-blockers, statins and antipsychotics (cf. [1]). Furthermore, adverse drug reactions (ADRs) frequently occur and cause about 7% of all hospital admissions, a frequency that is increased to 30% in elderly subjects above 70 years of age [2]. The ADRs cause on average 2 days of prolonged hospital visit and has been estimated to account for 100,000 deaths annually in the US (cf. [1]). It appears that the frequency of serious ADRs reported to the Food and Drug Administration (FDA) has doubled during the time period 1998–2005 [3] whereas the prescription of drugs has only increased by about 20% during the same time period. The major factor known today for interindividual differences in drug response is variable pharmacokinetics, which is mainly due to differences in the activity of cytochrome P450 enzymes involved in the metabolism of clinically used drugs. This area has been in focus of research at Karolinska Institutet since the mid-1970s and in the current presentation we describe some major achievements in this area and their clinically important aspects.

Section snippets

Cytochromes P450

The cytochrome P450 enzymes are important for the metabolism of both endogenous and exogenous compounds. There are 57 active genes in the human genome and enzymes in families 1–3 are particularly active in the detoxification of exogenous chemicals, whereas P450s in families 4–51 are mainly active in the metabolism of endogenous compounds like sterols, steroids, bile acids and fatty acids. At Karolinska Institutet, research in the P450 area was conducted from the mid-1970s by the groups of Henry

Cytochrome P450 and drug metabolism

Interindividual differences in response to a xenobiotic was perhaps first described by Pythagoras in 510 BC. He noted that some individuals developed haemolytic anaemia in response to fava bean ingestion. In 1902, Gorrod and Oxon [7] suggested genetic components being of importance in biochemical processes and they suggested that interindividual differences in ADRs were due to enzyme deficiencies, an idea further emphasized by Motulsky in 1957 [8], and in 1959 Vogel [9] coined the term

The human CYP-allele nomenclature database

The CYP-allele web page (The Home Page of the Human Cytochrome P450 (CYP) Allele Nomenclature Committee) is hosted by us at Karolinska Institutet (www.cypalleles.ki.se) and forms a database for the international nomenclature of P450 alleles. We continuously get new submissions to this page and the submissions are peer reviewed before publication on the web site which often precedes the publication in the scientific papers. The number of visits is relatively constant over time and amounts to

CYP2D6

The polymorphic metabolism of the CYP2D6 substrates like debrisoquine, nortriptyline and desimipramine was early recognized. In 1967, Folke Sjöqvist and collaborators from Karolinska Institutet reported a high interindividual variability to metabolise nortriptyline and desimipramine [13]. They observed tremendous interindividual differences in the plasma levels of the drugs, following administration of the same dosage. Subsequently, two poor metabolisers were identified. A basic point at that

Karolinska Institutet in Addis Abeba

The senior author of this review was the chairman of the Karolinska Institutet Research and Training Committee in 1998–1994. One of the tasks was to build up an educational and research platform in Addis Abeba together with colleagues and with finances from Sarec/Sida. Among other initiatives a Masters programme in medicine was started and one student, Eleni Aklillu, was admitted to this programme. In her research work she brought many blood samples from Ethiopia to Karolinska Institutet for

CYP2C19

CYP2C19 metabolises drugs belonging to the antiulcer, antiepileptic and antidepressant classes. The molecular basis behind CYP2C19 poor metabolism has been known for more than 15 years and is mainly represented by the CYP2C19*2 allele in Europeans and in addition by CYP2C19*3 in Asians. It was however over 10 years later when the CYP2C19*17 allele, leading to an increased rate of transcription and increased metabolism, was discovered at the Karolinska Institutet [31]. The allele causes higher

Genetic biomarkers for a more efficient drug therapy

In general it is now emphasized that drug treatment should not be population-based but rather based on the individual patients’ capability to respond to the drug treatment. Guidelines for pharmacogenomics in drug development have been published at FDA and are also to be released in 2010 by EMEA. The recommendations are to use pharmacogenomic biomarkers in different stages in (i) a mandatory manner, (ii) by recommendation, or (iii) for information purpose only. Of 1200 drug labels reviewed

Conclusions

The knowledge about P450 enzyme polymorphism has turned out to be of great importance for drug development and for effective drug treatment (cf. Table 1). Interaction with the polymorphic P450 enzymes are screened for routinely early in drug development and yet more examples where novel drugs are influenced by P450 polymorphism in a clinically important way are detected. We believe that this information will be translated into the clinical routine situation in the years to come, the

Acknowledgments

The research in the authors’ laboratory is supported by Grants from The Swedish Research Council, The Swedish Cancer Society, Vinnova, Hjärnfonden and from Torsten and Ragnar Söderbergs Stiftelser.

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