Physiological Turnover Models

FIGURE 20.7 Non-zero-asymptote model with natural history (thick line) offset pattern (thin line), and tu o types of protective pattern drug effects SSS, effect on steady-state burned out state (dashed line), and Tprog, effect on half-life of disease progress (dotted line). 

MaxProg is a parameter that determines the fractional change in at infinite time. The effect of a drug (PDI) might be to inhibit loss, in which case PDI would be modeled by Equation 20.19, where Cg,A is the effect site concentration and C50 is the value of Cg,A causing a 50% inhibition of loss  

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Lion Biosciences is the supplier of the iDEA Metabolism software package as well as other ADME/T services (289). The iDEA software simulates metabolism and predicts a compound s metabolic behavior in humans. The Metabolism Module consists of a data expert module to perform data fitting and analysis of collected in vitro data and the physiological metabolism model. The physiological metabolism model is constructed from proprietary database of 64 clinically tested compounds. Additionally, the metabolism module automatically calculates the Michaelis-Menten constants Km and VjIiax for the kinetic analysis of metabolism turnover (289). 

The Leggett Model simulates lead biokinetics in liver with two compartments the first simulates rapid uptake of lead from plasma and a relatively short removal half-life (days) for transfers to plasma and to the small intestine by biliary secretion a second compartment simulates a more gradual transfer to plasma of approximately 10% of lead uptake in liver. Different transfer rates associated with each compartment are calibrated to reproduce patterns of uptake and retention of lead observed in humans, baboons, and beagles following intravenous injection, as well as blood-to-liver concentration ratios from data on chronically exposed humans. Similarly, the Leggett Model simulates lead biokinetics in three compartments of soft tissues, representing rapid, intermediate, and slow turnover rates (without specific physiologic correlates). 

The kinetic approach requires choosing a mathematical model that can be fitted to the experimental data. A properly chosen model will allow calculation of turnover of metabolic and excretional pools. Further, one can calculate the various pool sizes. However, the model is nothing but a model and does not necessarily have any resemblance to physiological or medical circumstances. 

The effect of age on percutaneous absorption has been examined in vivo in man with variable results. It was postulated (Roskos et al. 1989) that reduced hydration levels and lipid content of older skin may be responsible for a demonstrated reduction in skin permeability where the permeants were hydrophilic in nature (no reduction was seen for model hydrophobic compounds) (Table 14.2). The reduced absorption of benzoic acid demonstrated in the elderly (Rougier 1991) was in line with this suggestion, but not the reduction in absorption of testosterone (lipophilic) (Roskos et al. 1986), or lack of change in the absorption of methyl nicotinate (more hydrophilic) with age (Guy et al. 1983). There are a number of potential physiological changes which may be responsible for age-related alterations, including an increase in the size of individual stratum corneum corneocytes, increased dehydration of the outer layers of the stratum corneum with age, decreased epidermal turnover and decreased microvascular clearance (reviewed in Roskos and Maibach 1992). The issue of age-related variability, however, is far from resolved. 

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