Cytochrome P450's pharmacogenetics in drug development and clinical aspects [review]

ABSTRACT

cytochrome P450s [CYPs] are members associated heme protein and hepatic microsomal enzymes, which play important role in drugs metabolism and detoxification. Seven of the 57 known human isoforms of P450s responsible for metabolism of more than 90% of the currently used drugs, CYP1A2, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1 and CYP3A4. Some. of them, CYP2D6, CYP2C9 and CYP2C19, have been shown to be polymorphic as a result of single nuclcotide polymorphisms [SNPs], gene deletions, and gene duplications. The effect of the polymorphisms ranges from a complete loss of functional protein to an increase in enzyme activity and can impact the drug development and clinical application. Most pharmaceutical companies have increasingly screened out compounds that are metabolized solely by polymorphic CYPs. Retrospective studies showed that one of the major causes of the new chemical entities [NCE] failure to reach the clinical stage was related to pharmacokinetic and toxicological issues. Therefore the industry has invested in the science and technology of absorption, distribution, metabolism, excretion and toxicity [ADMET] in order to reduce NCE attribution rates.. Drug metabolism is the most important determinant of the ADMET of most compounds and the role CYP450 is predominant. Overall, current trends in the industry have been fueled by increased managed healthcare, the desire to minimize the need for therapeutic drug monitoring and CYP genotyping in medical practice, and a very competitive marketplace