Tissue metabolism simulator TIMES

In-vitro models can provide preliminary insights into some pharmacodynamic aspects. For example, cultured Caco 2 cell lines (derived from a human colorectal carcinoma) may be used to simulate intestinal absorption behaviour, while cultured hepatic cell lines are available for metabolic studies. However, a comprehensive understanding of the pharmacokinetic effects vfill require the use of in-vivo animal studies, where the drug levels in various tissues can be measured after different dosages and time intervals. Radioactively labelled drugs (carbon-14) may be used to facilitate detection. Animal model studies of human biopharmaceutical products may be compromised by immune responses that would not be expected when actually treating human subjects. 

As with classic compartment pharmacokinetic models, PBPK models can be used to simulate drug plasma concentration versus time profiles. However, PBPK models differ from classic PK models in that they include separate compartments for tissues involved in absorption, distribution, metabolism and elimination connected by physiologically based descriptions of blood flow (Figure 10.1). 

Male Fischer 344/N rats were exposed via the nose only for 6 h to concentrations of vinylidene fluoride ranging from 27 to 16 000 ppm [71-42 000 mg/m. Tidal volume (mean, 1.51 mL/brcath) and respiratory frequency (mean, 132 breaths/min) were not influenced by exposure concentration. Steady-state blood levels of vinylidene fluoride increased linearly with increasing exposure concentration up to 16 000 ppm. Vinylidene fluoride tissue/air partition coefficients were determined experimentally to be 0.07, 0.18, 0.8,10, and 0.29 for water, blood, liver, fat and muscle, respectively. Previously published detenninations (Filser Bolt, 1979) for the maximum velocity of metabolism in mg/li/kg) and Michaelis Menten constant (K in mg/L) are 0.07 and 0.13, respectively. Time to reach steady-state blood levels of vinylidene fluoride was less than 15 min for all concentrations. After cessation of exposure, blood levels of vinylidene fluoride decreased to 10% of steady-state levels within 1 h. Simulation of the metabolism of vinylidene fluoride mdicated that although blood levels of vinylidene fluoride increased linearly with increasing exposure concentration, the amount of vinylidene fluoride metabolized per 6-h exposure period approached a maximum at about 2000 ppm [5240 mg/m vinylidene fluoride (Medinsky et al., 1988). 

Physiologically-Based Pharmacokinetics. Tissue-plasma partition coefficients may be calculated automatically by using only log P and fraction unbound in plasma as inputs. This module allows the user to simulate Cp vs. time profiles for drugs in discovery using only in silico or in vitro (metabolism) data inputs. 

Determination of exposure and toxic effects of chemicals also requires knowledge of toxicokinetics. Toxicokinetics is the study of changes in the levels of toxic chemicals and their metabolites over time in various fluids, tissues, and excreta of the body, and determines mathematical relationships to explain these processes. These processes depend upon uptake rates and doses, metabolism, excretion, internal transport, and tissue distribution. Methods for determining these processes include studies with laboratory animals, volunteer human subjects, persons accidentally exposed to high doses of chemicals, and experiments with tissue or organs cultured in the laboratory. Computer simulations of such processes are often formulated using complex mathematical equations. 

Model refinement and validation for both the chltnpyrifos and the diazinon PBPK/PD models wa.s accomplished by conducting a scries of in vivo pharmacokinetic and pharmacodynamic studies in the rat and by evaluating the capability of the model to accurately simulate in vivo data published in the literature. The experimental details are fully described in Timchalk et ai (2002b) and Poet et at. (2004). In brief, these studies involved an acute oral exposure to chlorpyrifos or diazinon and the blood time course of the parent compounds and metabolites was determined, as well as the time course for the cholinesterase inhibition in several tissues. Representative results and model simulations are presented in Fig. 12 and 13 for the pharmacokinetic and pharmacodynamic response in rats following comparable oral doses (50 and 100 mg/kg) of chlorpyrifos and diazinon, respectively, The overall response was fairly comparable for these two insecticides, and the models reasonably simulated both dosimetry and the dose-dependent cholinesterase inhibition. These results arc very consistent with a fairly rapid oral absorption for both insecticides and subsequent metabolism and distribution of the active oxon metabolites. Figure 14 illustrates the capability of the diazinon PBPK/PD model to simulate rodent dosimetry data from the open literature and the capability of the model to accommodate alternative exposure routes (Poet et ai, 2004). In these examples, the time course of diazinon in plasma and cholinesterase inhibition in tissues (i.e.. blood,... 

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