A Multicompartment Liver-based Pharmacokinetic Model for Benzene and its Metabolites in Mice

Abstract

Benzene is a highly flammable, colorless liquid, and ubiquitous exposures result from its presence in gasoline vapors, cigarette smoke, and industrial processes. After uptake into the body, benzene undergoes a series of metabolic transformations resulting in multiple metabolites that exert toxic effects on the bone marrow. We developed a physiologically based pharmacokinetic model for the uptake and elimination of benzene in mice to relate the concentration of inhaled and orally administered benzene to the tissue doses of benzene and its key metabolites. This model takes into account the zonal distribution of enzymes and metabolisms in the liver, rather than treating the liver as one homogeneous compartment, and considers metabolism in tissues other than the liver. Analysis was done to examine the existence and uniqueness of solutions of the system. We then formulated an inverse problem to obtain estimates for the unknown parameters; data from multiple laboratories and experiments were used. Despite the sources of variability, the model simulations matched the data reasonably well in most cases, showing that the multicompartment metabolism model does improve predictions over the previous model [6] and that in vitro metabolic constants can be successfully extrapolated to predict in vivo data for benzene metabolism and dosimetry.

In vivo validation of DNA adduct formation by estragole in rats predicted by physiologically based biodynamic modelling

“…Liver zonation dividing the liver compartment within the PBBD model into three equal zones: The liver architecture in vivo is not as homogenous as hepatocytes cultured in vitro. The heterogeneity of the liver implies that relevant biotransformation enzymes may be expressed in different parts of the organ to a different extent (20). The liver is mainly divided in a periportal zone (Zone 1), a mid-zone (Zone 2) and a perivenous zone (Zone 3).…”

“…All these rat CYPs are more active in the perivenous zone of the liver as compared with the other zones (23). UDP glucuronosyltransferase (UGTs) are expressed in the perivenous zone (20,24) but also in the periportal zone (25,26). SULT enzymes are expressed preferentially in the periportal zone (20,24).…”

“…UDP glucuronosyltransferase (UGTs) are expressed in the perivenous zone (20,24) but also in the periportal zone (25,26). SULT enzymes are expressed preferentially in the periportal zone (20,24). To accommodate both possible locations of the UGTs two zonal models were described one with the UGTs in the perivenous zone (Zone 3) and another with the location of the UGTs in the periportal zone (Zone 1).…”

“…Figure 3 presents a schematic overview of the refined model. The liver was described as three equal zones as explained in Manning et al (20), where each zone differs in the overall expression of the enzymes involved in the metabolism of estragole and 1'-OHES. The activity of each enzyme was confined to only the specific zone where it is most highly expressed, with exception of the UGTs that were modelled in either Zone 1 or Zone 3.…”

A computational investigation of the ventilation structure and maximum rate of metabolism for a physiologically based pharmacokinetic (PBPK) model of inhaled xylene

“…Physiologically based pharmacokinetic (PBPK) modeling uses ordinary differential equations to describe absorption, distribution, metabolism, and excretion of toxicants following exposure. PBPK models have been developed to estimate internal doses for various toxicants in rodents [1] [9] [11] [14] [17] [18] [25] [34] [37] [40] and in humans [2] [3] [8] [10] [13] [15] [23] [26] [35] [36] [39] [38] [43] [48]. Most PBPK model equations use the same basic structure and assumptions, such as the assumption that compartments are well-mixed and that the transfer of some chemicals is at equilibrium.…”