Evaluation of drug interactions and their metabolism by cytochromes P450
Almost one half of prospective drugs, including new chemical entities are not suitable for clinical use because of their metabolic instability and for danger of drug interactions. This type of toxicity has been underlying several drug withdrawals in recent years and hence it is needed now to bring with any new compound proposed an information on its metabolism and on its interactions with major drug metabolizing enzyme systems namely with liver microsomal cytochromes P450 (CYP). Then, possibility of drug interactions with other drugs taken by the patient on the basis of drug metabolism may be evaluated to prevent significant losses in time, effort and money in drug development. The analysis of drug metabolism by individual CYPs, the possibility of drug interactions and of induction of individual CYP forms are performed with CYP in vitro systems with the respective substrates, inhibitors and inductors based on the recommendation of the U.S. Food and Drug Administration: (https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers).
Presence of drug-microsomal CYP interactions is first checked with human liver microsomal fraction. Then, possible influence of a drug on established CYP activities is studied in vitro. Possible formation of metabolite(s) and the role of individual CYP enzymes in this metabolism is then analyzed using the human liver microsomal fraction and human hepatocytes. Finally, systems expressing single CYP form (e.g. bactosomes, supersomes) are used to confirm the role of the specific CYP form in the respective metabolic process. Induction of CYP is achieved using human hepatocytes; in specific cases, a preliminary study on CYP induction may be performed with experimental animals (rats). Expression of the individual genes, protein expression and changes in the respective enzyme activities are evaluated by RT-PCR, Western blotting and by evaluating the enzyme activities. Wherever possible, high-throughput analytical technologies are applied.
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