Generic Physiologically Based Pharmacokinetic Research Articles

Prediction of Pharmacokinetics Prior to In Vivo Studies. II. Generic Physiologically Based Pharmacokinetic Models of Drug Disposition

Many in vitro data on physicochemical properties and specific absorption, distribution, metabolism, and elimination (ADME) processes are already available at early stages of drug discovery. These data about new drug candidates could be integrated/connected in physiologically based pharmacokinetic (PBPK) models to estimate a priori the overall plasma and tissue kinetic behaviors under in vivo conditions. The objective of the present study was to illustrate that generic PBPK models integrating such data can be developed in drug discovery prior to any in vivo studies. This approach was illustrated with three example compounds, including two lipophilic bases (diazepam, propranolol) and one neutral more hydrophilic drug (ethoxybenzamide). Distribution and liver metabolism were the processes integrated in the generic rat PBPK models of disposition. Tissue:plasma partition coefficients (Pt:ps) used for description of distribution were estimated from established tissue composition-based equations, which need only in vitro data on drug lipophilicity and plasma protein binding as sole input parameters. Furthermore, data on intrinsic clearance (CLint) determined in vitro with hepatocytes were scaled to the in vivo situation to estimate hepatic metabolic clearance. These prediction approaches were both incorporated in the PBPK models to enable automated estimation of distribution and liver metabolism for each drug studied. The generic PBPK models suggested can simulate a priori concentration–time profiles of plasma and several tissues after intravenous administrations to rat. The results indicate that most of the simulated concentration–time profiles of plasma and 10 tissues are in reasonable agreement with the corresponding experimental data determined in vivo (less than a factor of two). However, some more relevant deviations were observed for specific tissues (brain and gut for diazepam; liver and gut for ethoxybenzamide; lung for propranolol) because of important ADME processes were probably neglected in the PBPK models of these drugs. In this context, generic PBPK models were also used for mechanistic evaluations of pharmacokinetics for generating research hypotheses to understand these deviations. Overall, the present generic and integrative PBPK approach of drug disposition suggested as a tool for a priori simulations and mechanistic evaluations of pharmacokinetics has the potential to improve the selection and optimization of new drug candidates. © 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:1358–1370, 2002

Quantitative exposure assessment: application of physiologically-based pharmacokinetic (PBPK) modeling of low-dose, long-term exposures of organic acid toxicant in the brain

Our objective was to construct a physiologically-based pharmacokinetic (PBPK) model describing the kinetic behavior of 2,4-dichlorophenoxyacetic acid (2,4-D) on rats after long-term exposures to low doses. Our study demonstrated the model's ability to simulate uptake of 2,4-D in discrete areas of the rat brain. The model was derived from the generic PBPK model that was first developed for high-dose, single exposures of 2,4-D to rats or rabbits (Kim, C.S., Gargas, M.L., Andersen, M.E., 1994. Pharmacokinetic modeling of 2,4-dichlorophenoxyacetic acid (2,4-D) in rats and rabbits brain following single dose administration. Toxicol. Lett. 74, 189–201; Kim, C.S., Slikker, W., Jr., Binienda, Z., Gargas, M.L., Andersen, M.E., 1995. Development of a physiologically based pharmacokinetic (PBPK) model for 2,4-dichlorophenoxyacetic acid (2,4-D) dosimetry in discrete areas of the brain following a single intraperitoneal or intravenous dose. Neurotox. Teratol. 17, 111–120.), to which a subcutaneous (hypodermal) compartment was incorporated for low-dose, long-term infusion. It consisted of two body compartments, along with compartments for venous and arterial blood, cerebrospinal fluid, brain plasma and six brain regions. Uptake of the toxin was membrane-limited by the blood-brain barrier with clearance from the brain provided by cerebrospinal fluid ‘sink’ mechanisms. This model predicted profiles of 2,4-D levels in brain and blood over a 28-day period that compared well with concentrations measured in vivo with rats that had been given 2,4-D (1 or 10 mg/kg per day) with [ 14C]-2,4-D subcutaneously (s.c.) for 7, 14, or 28 days, respectively. This PBPK model should be an effective tool for evaluating the target tissue doses that may produce the neurotoxicity of organic acid toxicants after low-dose, long-term exposures to contaminated foods or the environment.

Quantitative low-dose assessment of seafood toxin, domoic acid, in the rat brain: application of physiologically-based pharmacokinetic (PBPK) modeling

The purpose of this study was to construct a physiologically based pharmacokinetic model and demonstrate its ability to predict low-dose uptake of domoic acid, a seafood contaminant, in discrete areas of the rat brain. The model we used was derived from the generic PBPK model of our previous studies with 2,4-dichlorophenoxyacetic acid ( Kim et al., 1994. Pharmacokinetic modeling of 2,4-dichlorophenoxyacetic acid (2,4-D) in rats and in rabbits brain following single dose administration. Toxicol. Lett. 74, 189; Kim et al., 1995. Development of a physiologically based pharmacokinetic model for 2,4-dichlorophenoxyacetic acid dosimetry in discrete areas of the rabbit brain. Neurotoxicol. Teratol. 17, 111), to which physiological- and chemical-specific parameters for domoic acid were applied. It incorporates two body compartments along with compartments for venous and arterial blood, cerebrospinal fluid, brain plasma and seven brain regions. Uptake of the blood-borne toxin is membrane-limited by the blood-brain barrier with clearance from the brain provided by cerebrospinal fluid `sink' mechanisms. This model generated predicted profiles of toxin level in brain and blood over a 1-h period that compared reasonably well with concentrations calculated from in vivo data of rats that had been given [ 3H]domoic acid intravenously ( Preston and Hynie, 1991. Transfer constants for blood–brain barrier permeation of the neuroexcitatory shellfish toxin, domoic acid. Can. J. Neurol. Sci. 18, 39). This PBPK model should be an effective tool for evaluating the target doses that produce the potential neurotoxicity of domoic acid found in foods.

Construction of a Physiologically Based Pharmacokinetic Model for 2,4-Dichlorophenoxyacetic Acid Dosimetry in the Developing Rabbit Brain

A physiologically based pharmacokinetic (PBPK) model that describes the kinetics of organic anions by using 2,4-dichlorophenoxyacetic acid (2,4-D) as a representative compound was constructed for the developing rabbit brain at near-term pregnancy (Gestation Day 30). The model consisted of brain, body, and venous and arterial compartments for the mother which were linked to the fetus by a placenta. Maternal brain compartments in the model were brain plasma, cerebrospinal fluid (CSF), and brain tissue including hypothalamus, caudate nucleus, hippocampus, forebrain, brainstem, and cerebellum. The fetus consisted of brain, body, amniotic fluid, and venous and arterial compartments. The maternal body had both a central and a deep compartment; the fetal body had only one compartment. Maternal blood flow to the fetus was modeled as blood flowing to the placenta, where it was equilibrated before it reached the fetus. The brain uptake was membrane-limited by the blood–brain barrier, with saturable clearance from the CSF into the venous blood by the choroid plexus in both fetus and mother. The model was used to compare concentrations of 2,4-D in maternal and fetal brain, maternal and fetal plasma, and amniotic fluid over time with experimental data from pregnant rabbits given 2,4-D intravenously (1, 10, or 40 mg/kg). The model adequately simulated the 2-hr time course of 2,4-D concentrations in both mother and fetus. With continued development, this generic PBPK model should be a useful tool for evaluating the safety of organic acid neurotoxicants in the developing brain.

Physiologically based pharmacokinetic modeling with dichloromethane, its metabolite, carbon monoxide, and blood carboxyhemoglobin in rats and humans

Dichloromethane (methylene chloride, DCM) and other dihalomethanes are metabolized to carbon monoxide (CO) which reversibly binds hemoglobin and is eliminated by exhalation. We have developed a physiologically based pharmacokinetic (PB-PK) model which describes the kinetics of CO, carboxyhemoglobin (HbCO), and parent dihalomethane, and have applied this model to examine the inhalation kinetics of CO and of DCM in rats and humans. The portion of the model describing CO and HbCO kinetics was adapted from the Coburn-Forster-Kane equation, after modification to include production of CO by DCM oxidation. DCM kinetics and metabolism were described by a generic PB-PK model for volatile chemicals ( Ramsey and Andersen, Toxicol. Appl. Pharmacol. 73, 159–175, 1984 ). Physiological and biochemical constants for CO were first estimated by exposing rats to 200 ppm CO for 2 hr and examining the time course of HbCO after cessation of CO exposure. These CO inhalation studies provided estimates of CO diffusing capacity under free breathing and for the Haldane coefficient, the relative equilibrium distribution ratio for hemoglobin between CO and O 2. The CO model was then coupled to a PB-PK model for DCM to predict HbCO time course behavior during and after DCM exposures in rats. By coupling the models it was possible to estimate the yield of CO from oxidation of DCM. In rats only about 0.7 mol of CO are produced from 1 mol of DCM during oxidation. The combined model adequately represented HbCO and DCM behavior following 4-hr exposures to 200 or 1000 ppm DCM, and HbCO behavior following 1 2 - hr exposure to 5160 ppm DCM or 5000 ppm bromochloromethane. The rat PB-PK model was scaled to predict DCM, HbCO, and CO kinetics in humans exposed either to DCM or to CO. Three human data sets from the literature were examined: (1) inhalation of CO at 50, 100, 250, and 500 ppm; (2) seven 1 2 - hr inhalation exposures to 50, 100, 250, and 500 ppm DCM; and (3) 2-hr inhalation exposures to 986 ppm DCM. An additional data set from human volunteers exposed to 100 or 350 ppm DCM for 6 hr is reported here for the first time. Endogenous CO production rates and the initial amount of CO in the blood compartment were varied in each study as necessary to give the baseline HbCO value, which varied from less than 0.5% to greater than 2% HbCO. The combined PB-PK model gave a good representation of the observed behavior in all four human studies. This comprehensive model should prove useful for examining coexposures to DCM and CO, for predicting HbCO time courses expected for intermittent exposures to DCM and/or CO, and for developing biological monitoring strategies for these two contaminants based on observed HbCO concentrations after exposure.