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Computational approaches for modeling human intestinal absorption and permeability.

ABSTRACT: Human intestinal absorption (HIA) is an important roadblock in the formulation of new drug substances. Computational models are needed for the rapid estimation of this property. The measurements are determined via in vivo experiments or in vitro permeability studies. We present several computational models that are able to predict the absorption of drugs by the human intestine and the permeability through human Caco-2 cells. The training and prediction sets were derived from literature sources and carefully examined to eliminate compounds that are actively transported. We compare our results to models derived by other methods and find that the statistical quality is similar. We believe that models derived from both sources of experimental data would provide greater consistency in predictions. The performance of several QSPR models that we investigated to predict outside the training set for either experimental property clearly indicates that caution should be exercised while applying any of the models for quantitative predictions. However, we are able to show that the qualitative predictions can be obtained with close to a 70% success rate.

SUBMITTER: Subramanian G

PROVIDER: S-EPMC2441499 | biostudies-literature | 2006 Jul

REPOSITORIES: biostudies-literature

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Computational approaches for modeling human intestinal absorption and permeability.

Subramanian Govindan G Kitchen Douglas B DB

Journal of molecular modeling 20060401 5

Human intestinal absorption (HIA) is an important roadblock in the formulation of new drug substances. Computational models are needed for the rapid estimation of this property. The measurements are determined via in vivo experiments or in vitro permeability studies. We present several computational models that are able to predict the absorption of drugs by the human intestine and the permeability through human Caco-2 cells. The training and prediction sets were derived from literature sources a ...[more]

PMID: 16583199

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Project description:BackgroundUnderstanding the quantitative relationship between a drug's physical chemical properties and its rate of intestinal absorption (QSAR) is critical for selecting candidate drugs. Because of limited experimental human small intestinal permeability data, approximate surrogates such as the fraction absorbed or Caco-2 permeability are used, both of which have limitations.MethodsGiven the blood concentration following an oral and intravenous dose, the time course of intestinal absorption in humans was determined by deconvolution and related to the intestinal permeability by the use of a new 3 parameter model function ("Averaged Model" (AM)). The theoretical validity of this AM model was evaluated by comparing it to the standard diffusion-convection model (DC). This analysis was applied to 90 drugs using previously published data. Only drugs that were administered in oral solution form to fasting subjects were considered so that the rate of gastric emptying was approximately known. All the calculations are carried out using the freely available routine PKQuest Java (http://www.pkquest.com) which has an easy to use, simple interface.ResultsTheoretically, the AM permeability provides an accurate estimate of the intestinal DC permeability for solutes whose absorption ranges from 1% to 99%. The experimental human AM permeabilities determined by deconvolution are similar to those determined by direct human jejunal perfusion. The small intestinal pH varies with position and the results are interpreted in terms of the pH dependent octanol partition. The permeability versus partition relations are presented separately for the uncharged, basic, acidic and charged solutes. The small uncharged solutes caffeine, acetaminophen and antipyrine have very high permeabilities (about 20 x 10-4 cm/sec) corresponding to an unstirred layer of only 45 μm. The weak acid aspirin also has a large AM permeability despite its low octanol partition at pH 7.4, suggesting that it is nearly completely absorbed in the first part of the intestine where the pH is about 5.4.ConclusionsThe AM deconvolution method provides an accurate estimate of the human intestinal permeability. The results for these 90 drugs should provide a useful benchmark for evaluating QSAR models.

Project description:BACKGROUND: Intestinal morphology and function vary geographically. AIMS: These functions were assessed in asymptomatic volunteers in European, North American, Middle Eastern, Asian, African, and Caribbean countries. METHODS: Five hour urine collections were obtained from each subject following ingestion of a 100 ml iso-osmolar test solution containing 3-0-methyl-D-glucose, D-xylose, L-rhamnose, and lactulose after an overnight fast, to assess active (3-0-methyl-D-glucose) and passive (D-xylose) carrier mediated, and non-mediated (L-rhamnose) absorption capacity, as well as intestinal permeability (lactulose:rhamnose ratio). RESULTS: A comparison of results for subjects from tropical countries (n=218) with those resident in the combined temperate and subtropical region (Europe, United States, Qatar) (n=224) showed significant differences. Residents in tropical areas had a higher mean lactulose:rhamnose ratio and lower mean five hour recoveries of 3-0-methyl-D-glucose, D-xylose, and L-rhamnose, indicating higher intestinal permeability and lower absorptive capacity. Investigation of visiting residents suggested that differences in intestinal permeability and absorptive capacity were related to the area of residence. Subjects from Texas and Qatar, although comprised of several ethnic groups and resident in a subtropical area, showed no significant difference from European subjects. CONCLUSIONS: There are clearly demarcated variations in intestinal permeability and absorptive capacity affecting asymptomatic residents of different geographical areas which correspond with the condition described as tropical enteropathy. Results suggest the importance of environmental factors. The parameters investigated may be relevant to the predisposition of the indigenous population and travellers to diarrhoeal illness and malnutrition. Intestinal function in patients from the tropics may be difficult to interpret, but should take into account the range of values found in the asymptomatic normal population.

Project description:Iron is a trace metal, key for the development of living organisms. Its absorption process is complex and highly regulated at the transcriptional, translational and systemic levels. Recently, the internalization of the DMT1 transporter has been proposed as an additional regulatory mechanism at the intestinal level, associated to the mucosal block phenomenon. The short-term effect of iron exposure in apical uptake and initial absorption rates was studied in Caco-2 cells at different apical iron concentrations, using both an experimental approach and a mathematical modeling framework. This is the first report of short-term studies for this system. A non-linear behavior in the apical uptake dynamics was observed, which does not follow the classic saturation dynamics of traditional biochemical models. We propose a method for developing mathematical models for complex systems, based on a genetic programming algorithm. The algorithm is aimed at obtaining models with a high predictive capacity, and considers an additional parameter fitting stage and an additional Jackknife stage for estimating the generalization error. We developed a model for the iron uptake system with a higher predictive capacity than classic biochemical models. This was observed both with the apical uptake dataset used for generating the model and with an independent initial rates dataset used to test the predictive capacity of the model. The model obtained is a function of time and the initial apical iron concentration, with a linear component that captures the global tendency of the system, and a non-linear component that can be associated to the movement of DMT1 transporters. The model presented in this paper allows the detailed analysis, interpretation of experimental data, and identification of key relevant components for this complex biological process. This general method holds great potential for application to the elucidation of biological mechanisms and their key components in other complex systems.

Project description:Improvements in quantitative measurements of human physical activity are proving extraordinarily useful for studying the underlying musculoskeletal system. Dynamic models of human movement support clinical efforts to analyze, rehabilitate injuries. They are also used in biomechanics to understand and diagnose motor pathologies, find new motor strategies that decrease the risk of injury, and predict potential problems from a particular procedure. In addition, they provide valuable constraints for understanding neural circuits. This paper describes a physics-based movement analysis method for analyzing and simulating bipedal humanoid movements. The model includes the major body segments and joints to report human movements' energetic components. Its 48 degrees of freedom strike a balance between very detailed models that include muscle models and straightforward two-dimensional models. It has sufficient accuracy to analyze and synthesize movements captured in real-time interactive applications, such as psychophysics experiments using virtual reality or human-in-the-loop teleoperation of a simulated robotic system. The dynamic model is fast and robust while still providing results sufficiently accurate to be used to animate a humanoid character. It can also estimate internal joint forces used during a movement to create effort-contingent stimuli and support controlled experiments to measure the dynamics generating human behaviors systematically. The paper describes the innovative features that allow the model to integrate its dynamic equations accurately and illustrates its performance and accuracy with demonstrations. The model has a two-foot stance ability, capable of generating results comparable with an experiment done with subjects, and illustrates the uncontrolled manifold concept. Additionally, the model's facility to capture large energetic databases opens new possibilities for theorizing as to human movement function. The model is freely available.

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Computational approaches for modeling human intestinal absorption and permeability.

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Computational approaches for modeling human intestinal absorption and permeability.

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