Host: The Japanese Society of Toxicology
Name : The 51st Annual Meeting of the Japanese Society of Toxicology
Date : July 03, 2024 - July 05, 2024
Evaluation of hepatic cytochrome P450 (P450)-mediated fractions metabolized of drugs is important for evaluating drug interactions and effect modifiers in pharmacogenetics. In an in vitro system, ~80% inhibition of single-on-target P450 activity in human liver microsomes pretreated with time-dependent inhibitors was observed under limited off-target effects. Sustained experimental human hepatocytes (HepaSH cells) harvested from quality-controlled transplanted mice are available. R- and S-Omeprazole 5-hydroxylation by human P450 2C19 in HepaSH cells was slightly (~2-fold) autoinduced by R,S-omeprazole. Modeled hepatic/plasma exposure to omeprazole in subjects with P450 2C19 poor metabolizers is likely associated with hepatic toxicity. Humanized-liver mouse systems pretreated with furafylline and tienilic acid would be useful, creating a standard in vivo animal model to investigate the contributions of specific P450 1A2 and 2C9, and some apparent contradictions were observed for P450 2D6 and 3A4 (the in vivo fraction metabolized in hepatocytes treated with paroxetine and azamulin and the in vitro fraction metabolized). Similarly, unexpectedly high hepatic exposure modeled with data from the paroxetine pretreatment-humanized liver mouse model, possibly in intermediate-metabolizer patients harboring P450 2D6*10, may contribute to the adverse effects recorded for atomoxetine prescribed alone.
