Physiologically Based Pharmacokinetic (PBPK) Modeling of Metabolic Pathways of Bromochloromethane in Rats.

Bromochloromethane (BCM) is a volatile compound and a by-product of disinfection of water by chlorination. Physiologically based pharmacokinetic (PBPK) models are used in risk assessment applications. An updated PBPK model for BCM is generated and applied to hypotheses testing calibrated using vapor uptake data. The two different metabolic hypotheses examined are (1) a two-pathway model using both CYP2E1 and glutathione transferase enzymes and (2) a two-binding site model where metabolism can occur on one enzyme, CYP2E1. Our computer simulations show that both hypotheses describe the experimental data in a similar manner. The two pathway results were comparable to previously reported values (V(max⁡) = 3.8 mg/hour, K(m) = 0.35 mg/liter, and k(GST) = 4.7 /hour). The two binding site results were V(max⁡(1) ) = 3.7 mg/hour, K(m⁡(1) ) = 0.3 mg/hour, CL(2) = 0.047 liter/hour. In addition, we explore the sensitivity of different parameters for each model using our obtained optimized values.

A multicompartment geometric model of the liver in relation to regional induction of cytochrome P450s.

A geometric, multicompartment model of the liver was developed to examine regional protein induction and to provide model output suitable for predicting the degree of induction in both the whole liver and in specific regions. The model was based on functional hexagonal arrays within the liver. A geometric representation was used to divide these functional units into five zones: a concentric periportal zone, a fenestrated periportal region that interconnects among multiple functional units, and three concentric centrilobular areas, referred to, respectively, as zones 1 through 5. The surface areas (and volumes for hexagonal cylinders) of these live zones were, respectively, 13.5, 25.2, 33.9, 20.3, and 6.8% of the total liver. The pharmacokinetic model for induction had dissociation constants (Kd) and Hill constants (n) for interactions of transcriptional activator-ligand complexes with response elements on DNA. Estimates of regional induction were converted to color intensities to "paint" the two-dimensional liver for a visual comparison with immunohistochemical observations. To obtain sharp moving boundaries of induced areas with increasing dose (as noted in various experiments), n values in each subcompartment must be large. To create realistic total induction curves that are relatively smooth, the differences in Kd values between adjacent subcompartments must be less than fivefold. Because of the high n values, the low-dose induction characteristics predicted with the multicompartment liver model differ significantly from those predicted with a model that considers the liver as a single homogeneous compartment.

Regional hepatic CYP1A1 and CYP1A2 induction with 2,3,7,8-tetrachlorodibenzo-p-dioxin evaluated with a multicompartment geometric model of hepatic zonation.

A physiologically based pharmacokinetic (PBPK) model for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was combined with a five-compartment geometric model of hepatic zonation to predict both total and regional induction of CYP450 proteins within the liver. Three literature studies on TCDD pharmacokinetics and protein induction in female rats were analyzed. In simulating low-dose behavior for mRNA in whole liver and, particularly, in representing immunohistochemical observations, the five-compartment model was more successful than conventional homogeneous one-compartment liver models. The five-compartment liver model was used with the affinity of TCDD for the Ah receptor (AhR) held constant across all the liver (Kb = 0.2 nM). The presumed affinities of the AhR-TCDD complex for TCDD responsive elements in the CYP1A1 (Kd1) and CYP1A2 (Kd2) genes varied between adjacent compartments by a factor of 3. This parameterization leads to predicted 81-fold differences in affinities between the centrilobular and the periportal regions. The affinities used for AhR-TCDD complex binding to TCDD response elements for CYP1A2 in compartment 3 (the midzonal area) ranged from 0.08 to 1.0 nM in the three studies modeled. For CYP1A1 the corresponding dissociation constant in compartment 3 varied from 0.6 to 2.0 nM. In each compartment, the Hill coefficient for induction had to be 4 or greater to match the immunohistochemical results. This multi-compartment liver model is consistent with data on protein and mRNA induction throughout the liver and on the regional distribution of these proteins. No previous model has incorporated regional variations in induction. The PBPK analysis based on the multicompartment liver model suggests that the low-dose behavior for hepatic CYP1A1/CYP1A2 induction by TCDD is highly non-linear.