Pharmacogenetic diagnostics of cytochrome P450 polymorphisms in clinical drug development and in drug treatment.
The current use and future perspectives of molecular genetic characterisation of cytochrome P450 enzymes (CYP) for drug development and drug treatment are summarised. CYP genes are highly polymorphic and the enzymes play a key role in the elimination of the majority of drugs from the human body. Frequent variants of some enzymes, CYP2A6, 2C9, 2C19 and 2D6, should be analysed in participants of clinical trials whenever these enzymes may play a role. It is suggested that a CYP genotype certificate is handed out to the volunteers or patients to avoid replicate analyses, and to allow that this information is available for future research and also for treatment with eventually needed drugs. Guidelines on what CYP alleles have to be analysed in drug development, as well as on analytical validation and CYP genotype data handling will be required. Treatment with several drugs may be improved by prior genotyping. The concepts and problems of CYP genotype-based clinical dose recommendations are presented and illustrated for selected drugs. The requirement for prospective trials on the medical and economic benefits of routine CYP genotyping is emphasised. Specific operationally defined recommendations dependent on genotype are a prerequisite for such studies and this review presents tentative CYP genotype-based dose recommendations systematically calculated from published data. Because of the multiplicity of factors involved, these doses will not be the optimal doses for each given individual, but should be more adequate than doses generally recommended for an average total population. Those CYP alleles and polymorphically metabolised drugs which are currently most interesting in drug development and drug treatment are reviewed, and more complete information is available from websites cited in this article.
Institute of Clinical Pharmacology, University Medical Center Charité, Humboldt University, Berlin, Germany. jurgen.brockmöller@charite.de
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Brockmöller
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Kirchheiner
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Meisel
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Roots
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D004358:Drug Therapy; D006801:Humans; D010601:Pharmacology, Clinical; D011110:Polymorphism, Genetic / Q000235:genetics*
D003577:Cytochrome P-450 Enzyme System