A preliminary physiologically based pharmacokinetic model for naphthalene and naphthalene oxide in mice and rats.

摘要: Naphthalene is a toxicant with unusual species and tissue specificity that has been the subject ofin vitro studies. We describe preliminary physiologically based pharmacokinetic (PBPK) model for naphthalene constructed solely fromin data comparison to animal without use of adjustable parameters. The prototypical PBPK containing five lumped compartments was developed uptake metabolism by mice rats dosed intraperitoneally (ip) orally (po). incorporates circulation biotransformation semistable reactive intermediate, oxide, as well parent compound naphthalene. Circulation included because toxic action proposed be caused formation metabolite in one organ (liver) its another (lung) being adversely affected metabolite. allows conversion oxide into dihydrodiol, glutathione (GSH) conjugates, 1-naphthol (nonenzymatically) covalently bound adducts proteins. Model simulations are compared previously reportedin vivo measurements depletion, mercapturic acid formation, protein formation. mouse predicts accurately amount mercapturates excreted, effect various pretreatments, extent covalent binding lung liver resulting from ip administration, including sharp increase between 200 400 mg/kg.