RESUMEN
A physiologically based pharmacokinetic (PBPK) model with five tissue groups (lung, liver, fat, richly perfused, and poorly perfused tissues plus venous and arterial blood compartments) has been developed from in vitro data and models of primary cell cultures for naphthalene toxicity in mice and rats. It extends a previous naphthalene PBPK model (Sweeney et al., 1996) and demonstrates a possible approach to a predictive mathematical model that requires minimal animal data. Naphthalene metabolism was examined after four exposure routes (intraperitoneal injection (ip), intravenous injection (iv), ingestion (po), and inhalation). Naphthalene and its primary metabolite, naphthalene oxide, are consumed by enzymes in pulmonary and hepatic tissues (cytochrome P450 monooxygenases, epoxide hydrolase, and glutathione-S-transferase). Additionally, the nonenzymatic reactions of naphthalene oxide in all tissues and in blood are included in the model. Kinetic constants for the model were derived primarily from cell fraction and primary cell culture incubations presented in the literature. The mouse model accurately predicts glutathione (GSH) and covalent naphthalene oxide-protein binding levels after a range of ip doses, and the rat model provides excellent estimates for mercapturate excretion following po doses; but neither model simulates well naphthalene blood concentrations after low iv doses. Good prediction of in vivo response using only in vitro data for parameter estimation (except for epoxide-protein binding rates) suggests that the assumed molecular description is a plausible representation of the underlying mechanisms of toxicity. Mice and rats show significant species differences in response to naphthalene. The model results suggest that species differences in toxicity may be explained, in part, by the lower overall rate of enzyme activities in the rat cells. Lower enzyme activities in the rat result in out-of-phase GSH minima in hepatic and lung compartments, while the simultaneous occurrence of these minima in mice results in higher naphthalene oxide concentrations, thereby allowing formation of more metabolites (e.g., covalent binding to proteins) that may be toxic.
Asunto(s)
Modelos Biológicos , Naftalenos/farmacocinética , Tejido Adiposo/metabolismo , Animales , Biotecnología , Glutatión/metabolismo , Técnicas In Vitro , Hígado/metabolismo , Pulmón/metabolismo , Ratones , Naftalenos/sangre , Naftalenos/toxicidad , Ratas , Especificidad de la Especie , Distribución TisularRESUMEN
Naphthalene is a toxicant with unusual species and tissue specificity that has been the subject of in vitro studies. We describe a preliminary physiologically based pharmacokinetic (PBPK) model for naphthalene constructed solely from in vitro data for comparison to animal data without the use of adjustable parameters. The prototypical PBPK model containing five lumped tissue compartments was developed to describe the uptake and metabolism of naphthalene by mice and rats dosed intraperitoneally (i.p.) and orally (po). The model incorporates circulation and biotransformation of the semistable reactive intermediate, naphthalene oxide, as well as the parent compound naphthalene. Circulation is included because the toxic action of naphthalene has been proposed to be caused by the formation of a reactive metabolite in one organ (liver) and its circulation to another organ (lung) being adversely affected by the metabolite. The model allows conversion of naphthalene oxide into dihydrodiol, glutathione (GSH) conjugates, 1-naphthol (non-enzymatically) and covalently bound adducts with proteins. Model simulations are compared with previously reported in vivo measurements of glutathione depletion, mercapturic acid formation, and covalently bound protein formation. The mouse model predicts accurately the amount of mercapturates excreted, the effect of various pretreatments, and the extent of covalent binding in the lung and liver resulting from ip administration, including the sharp increase in binding between 200 and 400 mg/kg.