A human PBPK model for ethanol describing inhibition of gastric motility

Abstract

A physiologically based pharmacokinetic model for investigating inter-individual and inter-racial variability in ethanol pharmacokinetics is presented. The model is a substantial modification of an existing model which described some genetic polymorphisms in the hepatic alcohol dehydrogenase enzymes. The model was modified to incorporate a description of ethanol absorption from the stomach and gastro-intestinal tract and the retardation of gastric emptying due to a concentration-dependent inhibition of gastric peristalsis. In addition, intra-venous and intra-arterial routes of administration were added to investigate whether the biological structure of the model provided a core which may be easily adapted for any route of exposure. The model is proposed as suitable for the investigation of the effects of both acute and chronic ethanol exposure.

MEGen: a physiologically based pharmacokinetic model generator

“…The human PBPK model describing intra-venous infusion and hepatic ethanol metabolism by cytochrome P450 and three isoforms of alcohol dehydrogenase (Pastino et al, 2000) was modified to simulate oral and intra-venous administration (Loizou and Spendiff, 2004). …”

“…The models were built using MEGen as described below. The experimental data points in Figures 5–7 of this report were obtained by digitizing Figure 2A of Himmelstein et al (2004), Figure 5 of Clewell et al (2001) and Figure 5 of Loizou and Spendiff (2004). …”

“… Reproduction of Figure 5 from Loizou and Spendiff (2004) . Simulated (line) versus measured (symbols) blood ethanol concentrations following intra-venous administration of 0.4 g kg −1 ethanol for 1 h. PBPK model exported in MATLAB version R2010b.…”

“…Exposure was by the intra-venous route and the output was compared to mean experimental blood ethanol concentrations from six adult subjects infused with 0.4 g kg −1 for 1 h (error bars not displayed; Figure 15). The model was built and exported in MATLAB syntax and run on that platform to reproduce Figure 5 from Loizou and Spendiff (2004; experience with MATLAB is recommended in order to run and plot the generated function model). Model construction, simulation, and graphical output were completed in about 10 min.…”

Modeling of Physiology Based Toxico-Kinetics and Toxico-Dynamic to Diagnose Acute Effects of Nicotine on Heart Rate

“…Where: These parameters values [13][14][15][16][17][18] are mentioned in Gajewska M et al [8] and Loizou et al [16] which are discussed in the references. The volume of the organ is calculated with the information of organ's weight and its density which are tabulated in Table 2.…”