Construction and activity of recombinant cythochrome P450 enzymes as an in vitro system for reaction-phenotyping of drug candidates in the Göttingen minipig.

During drug development, pharmaceutical companies are required to characterize all routes of clearance (drug elimination) in man. Although the characterization of the metabolic profile of a drug is only required prior to the start of Phase 3 clinical trials, earlier information is very useful for the species selection in safety studies. Therefore, in vitro drug metabolism studies in several species are often performed early during drug development. Liver microsomes or the S9 fraction are the most common tools for screening of effects of a new drug on the CYP450 pathways, although liver slices or isolated hepatocytes give a more complete picture. To unravel the specific isoenzymes involved in the metabolism of drugs, recombinantly expressed cDNA of several CYP isoforms is used and commercially available for a number of species, including man, mouse, rat, dog and monkey. For the minipig no recombinant CYPs are commercially available. This species is, however, increasingly used in juvenile and general toxicity studies. Therefore, the aim of our project is to develop recombinant CYP enzymes of the minipig and compare their activity with adult minipig liver microsomes and in vivo pharmacokinetic (PK) data. This minipig recombinant system can be very valuable for pharmaceutical companies for species selection in non-clinical studies.

Keywords:IN VITRO, DRUG METABOLISM

Disciplines:Biomarker discovery and evaluation, Drug discovery and development, Medicinal products, Pharmaceutics, Pharmacognosy and phytochemistry, Pharmacology, Pharmacotherapy, Toxicology and toxinology, Other pharmaceutical sciences