The goal of this study was to determine the most appropriate hydrodynamic model for the Loc‐I‐Gut in‐vivo perfusion system. The general mixing‐tank‐in‐series model, which can approximate single mixing tank and laminar and plug‐flow hydrodynamics, was fitted to the observed experimental residence‐time distribution curves for the non‐absorbable marker [14C]PEG 4000. The residence‐time distribution analysis shows that the hydrodynamics of the perfusion solution within the jejunal segment in man is well approximated by a model containing on average between 1–2 mixing tanks in series. The solution is well mixed when using perfusion rates of 20, 30 and 60 mL min−. The average mean residence time estimates from the fitted residence‐time distribution were 12 ± 7.6, 15 ± 4.2 and 7.7 ± 4.6 min, respectively, at these three perfusion rates. The mean volumes of the segment (Vs) were 25 ± 15, 45 ± 12 and 46 ± 27 mL, respectively. There were no statistical differences between 20, 30 and 60 mL min− in respect of the number of mixing tanks (n) and mean residence times. This residence‐time distribution analysis indicates that the luminal fluid in the Loc‐I‐Gut perfusion system is well‐mixed, and that permeability calculations based on the well‐mixed assumption most closely approximate the actual local (average) membrane permeability within the perfused segment.
Investigation of the underlying mechanism leading to inter- and intrasubject variations in the plasma concentration-time profiles of drugs (1) can considerably benefit rational drug therapy. The significant effect of gastric emptying on the rate and extent of celiprolol absorption and its role with respect to double-peak formation was demonstrated in the present study. In four dogs racemic celiprolol was dosed perorally in a crossover design during four different phases of the fasted-state gastric cycle and gastric motility was recorded simultaneously using a manometric measurement system. Intravenous doses were also given to obtain disposition and bioavailability parameters. The blood samples were assayed by a stereoselective HPLC method (2). The time to onset of the active phase of the gastric cycle showed an excellent correlation with the time to celiprolol peak concentration. Furthermore, bioavailability was increased when celiprolol was administered during the active phase. Double peaks were observed when the first active phase was relatively short, suggesting that a portion of the drug remained in the stomach until the next active phase. Population pharmacokinetic modeling of the data with a two-compartment open model with two lag times incorporating the motility data confirmed the effect of time to gastric emptying on the variability of the oral pharmacokinetics of celiprolol. The fasted-state motility phases determine the rate and extent of celiprolol absorption and influence the occurrence of double peaks. Peak plasma levels of celiprolol exhibit less variability if lag times, and therefore gastric emptying times, are taken into consideration.
Logarithmic sensitivity coefficients were promulgated for the analysis of metabolic regulation about 20 years ago. Interest in their use has risen significantly since their introduction. However, no comprehensive evaluation of the utility of these metabolic sensitivity coefficients is available for realistic metabolic models. In this study, logarithmic sensitivity coefficients calculated from three progressively simpler metabolic models of red blood cell metabolism were compared. Two simpler models were obtained from a comprehensive red cell model by first removing volume regulation, and second by removing two pathways. The comparisons of sensitivity coefficients obtained for these three models showed that model complexity has significant effects on the numerical values and interpretation of the metabolic sensitivity coefficients. Additionally, it was found that the physiochemical volume regulatory mechanism, namely electroneutrality and osmotic balances, play an important role in the red cell metabolic flux control. In general, there is no proportionate relationship between sensitivity coefficients calculated from the three different red cell metabolic models or other simple red cell models reported in the early literature. Some sensitivity coefficients determined by different models even have opposite signs. Thus, analysis of incomplete metabolic models can be seriously misleading and produce inappropriate indicators of the characteristics of a full model for the same metabolic network.
We have developed a computer software package for Macintosh to simulate the metabolism and hemoglobin binding affinity of human red blood cell. The model is capable of simulating hemoglobin binding of ligands, metabolite concentrations, and metabolic fluxes at physiological steady state and in response to extracellular parameter variations, such as pH, osmolarity, glucose, and adenine concentrations. The kinetic parameters of enzymes, extracellular conditions, and initial intracellular metabolite concentrations can be specified by the user in order to model a particular situation. The software is use friendly, utilizing menu, window, and mouse to interact with the user. It also provides a pathway map of the red cell, which allows a direct access to enzyme kinetics by clicking the enzymes in the map.
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