Clinical trials genotyping of CYP450, DME, drug targets, ...

Pharmacogenetics is the study of the influence of variations in DNA sequence on drug response (European Medicine Agency definition, Nov 2006).

Each enzyme, target or transporter involved in the pharmaco-kinetics, or – dynamics of a drug is encoded by a gene, which is a DNA sequence. All individual has two copies (two alleles) of each gene, one inherited from the mother, the other from the father. The two alleles may have the same DNA sequence or not. A polymorphism is a variation in the DNA sequence of a gene, which may involve one (heterozygote) or both alleles (homozygous) of the gene. A polymorphism in the gene encoding a CYP enzyme, drug transporter, receptor or target may result in the modification of the activity of CYP enzymes or alter the functions of drug’s transporter, receptor or targets.

Most drugs are metabolised by different enzyme systems known as phase I metabolism (functionalisation reactions) or phase II metabolism (conjugation reactions).

DME - Phase I Enzymes

The cytochrome P450 enzymes (CYP450) are the most widely studied phase I metabolizing enzymes. Polymorphisms resulting in poor (PM), intermediate (IM), normal (EM) or rapid metabolizers (UM) have mostly been studied in isoenzymes CYP2D6 and 2C19. Slow metabolisers have mutations which inactivate members of the CYP450 family, normal metabolisers carry 2 normal copies of the CYP450 gene, while fast metabolisers carry more than 2 genes (gene duplication) causing high levels of CYP450 expression or mutations which accelerated their function.

The DNAVision genotyping services deals with aspects of CYP450s relevant to human pharmacology and, in particular, with the detection of CYP mutants of functional importance in drug metabolism. Their large diversity has arisen by complex evolution, including gene duplication and other genetic mechanisms. CYPs, grouped according to the similarity of their amino acids, are involved in hepatic drug oxidation and belong to three families: CYP1, CYP2 and CYP3.

DME - Phase II Enzymes

Phase II conjugating enzymes (Daly, J Mol Med (1995) 73: 539-553) include uridine diphosphate glucuronyl-transferases (UGTs), sulfonyl transferases (SULTs), N-acetyltransferases type II (NAT2) and thiopurine methyltransferases (TPMTs). Most of these genes have polymorphisms changing the nature of their function. There are, for example, 2 functional N-acetyltransferase genes, NAT1 and NAT2. There are at least 3 major slow acetylator NAT2 alleles, 2 of which are common in Caucasians and one in Mongoloids.

Genotyping of Clinical Trials Volunteers/Patients

We genotype volunteers and patients participating in clinical trials.

The FDA and other regulatory agencies require clinical trial data on defined populations of subjects for new investigational drugs, so pharmaceutical companies, clinical research organizations and site management organizations have an immediate need for genotyping services. To help clients confirm safety and efficacy, DNAVision scientists use its leading DME assays panel - designed to capture 99% of the most important mutations that predict patient outcome - and other individual tests to categorize poor, intermediate, extensive or ultra-rapid metabolizers.

Most Requested Assays

Gene	Alleles available	Quality
CYP2D6	2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14A, 14B, 15, 17, 19, 20, 21, 24, 25, 26, 29, 30, 31, 35, 36, 38, 40, 41, 44, 1XN, 2XN, 4XN, 10XN, 17XN, 35XN, 41XN also available Roche Amplichip CYP450 IVD assay	ISO17025
CYP2C19	2, 2B, 3, 4, 5, 6,78, 9, 10, *11 also available Roche Amplichip CYP450 IVD assay	ISO17025
CYP2C9	2, 3, 4, 5,* 6, *11	ISO17025

Other Available Assays

All our assays are validated according ICH guidelines. If you are looking for another specific mutation/variant, please contact us.

We can develop, validate and accreditate a specific assay on your request.

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