A physiological and system analysis hybrid pharmacokinetic model to characterize carbon tetrachloride blood concentrations following administration in different oral vehicles

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Abstract
Oral absorption of chemicals can be influenced significantly by the administration vehicle or diluent. It has been observed that the oral absorption of carbon tetrachloride (CCl 4)and other volatile organic chemicals is markedly affected by the dosing vehicle, with administration in oils producing erratic blood concentration-time profiles with multiple peaks. Analysis of this type of data by a compartmental modeling approach can be difficult, and requires numerous assumptions about the absorption processes. Alternatively, a system analysis method with few assumptions may provide a more accurate description of the observed data. In the current investigations, a nonlinear system analysis approach was applied to blood CCl 4 concentration-time data obtained following iv and oral administration. The oral regimens consisted of 25 mg CCl 4/kgbody wt given as an aqueous emulsion, in water, as pure chemicals, and in corn oil. The system analysis procedure, based upon a disposition decomposition method, provided an absorption input rate function, F,for each regimen. A physiological pharmacokinetic model, based primarily on parameters available in the literature, and the Finput functions, formed a hybrid model that adequately described the observed blood CCl 4 concentration-time data. The same physiological pharmacokinetic model, employing conventional first-order absorption input schemes, did not predict the data as well. Overall, the system analysis approach allowed the oral absorption of CCl 4 to be characterized accurately, regardless of the vehicle. Though system analysis is based on general mathematical properties of a system's behavior rather than on its causal mechanisms, this work demonstrates that it can be a useful adjunct to physiological pharmacokinetic models.

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