Avaliação do metabolismo in vitro do CNFD (6b, 7-dihidro-5H-ciclopenta [b] nafto [2,1-d] furano-5,6 (9aH) - diona)

Abstract

Due to the impact of cancer on health systems and the adverse effects caused by antineoplastic drugs, several strategies have been investigated in the search for new drug prototypes, especially those originating from plants, which have generated substances with great therapeutic potential. In this context, lausone (2-hydroxy-1,4-naphthoquinone) and its derivatives, which are naphthoquinones with antitumor, antifungal, antimalarial, antiviral and antibacterial activity, stand out. CNFD (6b, 7-dihydro-5H-cyclopenta[b]naphtho[2,1-d]furan-5,6(9aH)-dione) is one of these derivatives, which showed potent antineoplastic activity in tumor cells in vitro and in vivo, being a promising candidate for a new drug. Thus, considering that it is a pharmacologically active compound, efforts should be directed towards investigating the metabolism stage in the early stages of development of this new chemical entity. For this research, firstly, a bioanalytical method using high performance liquid chromatography coupled to an ultraviolet absorption detector (HPLC-UV) was developed to quantify the compound in plasma and in human liver microsomes. In addition, data on enzyme kinetics, predicted in vivo pharmacokinetic parameters and the phenotyping study were presented. The main sites of metabolism and metabolites were suggested in silico. The HPLC method developed with the microsomal matrix was linear, reproducible, selective, accurate and stable. The enzyme kinetic parameters revealed a sigmoidal profile. The hepatic metabolic clearance was 10.39 mL min-1 kg-1 of protein and the hepatic extraction rate was 51%. In vivo clearance associated with a hepatic extraction ratio indicates that hepatic metabolism is the major route of elimination. Although all the cytochrome P450 enzymes evaluated metabolized CNFD, CYP2C9 and CYP3A4 isoforms showed greater metabolic capacity. The metabolism of CNFD was described for the first time and will serve as a starting point for further studies of enzyme inhibition and in vivo pharmacokinetics.