Gastrointestinal simulation

Physiologically based mechanistic gastrointestinal simulation can be used for identification and ranking of drug discovery candidates with regard to their lib-... 

Kovacevic I, Parojcic J, Homsek I et al (2009) Justification of bio waiver for carbamazepine, a low soluble high permeable compound, in solid dosage forms based on IVIVC and gastrointestinal simulation. Mol Pharm 6 40-47... 

Other than the different approaches mentioned above, commercial packages such as GastroPlus (Simulations Plus, Lancaster, CA) [19] and IDEA (LionBioscience, Inc. Cambridge, MA) [19] are available to predict oral absorption and other pharmacokinetic properties. They are both based on the advanced compartmental absorption and transit (CAT) model [20], which incorporates the effects of drug moving through the gastrointestinal tract and its absorption into each compartment at the same time (see also Chapter 22). 

After treatment under the conditions simulating the gastrointestinal lumen pectin was depo-lymerized only to a small extent. 

The model is designed to simulate inhalation exposures to americium however, it could be applied to ingestion exposures since the model simulates the absorption of americium from the gastrointestinal tract. The model cannot be applied to other routes of exposure without modification. 

An interesting paper that attempted to relate dissolution of a poorly soluble acidic drug (naproxen) to simulated gastrointestinal flow in the presence of buffers was published by Chakrabarti and Southard [17]. In addition to showing that buffer type (citrate, phosphate, or acetate) had a significant impact on naproxen dissolution, these authors unexpectedly found that elevating a solid tablet into the flow channel of the flow-between-two-plates apparatus resulted in a substantial... 

S Chakrabarti, MZ Southard. Control of poorly soluble drug dissolution in conditions simulating the gastrointestinal tract flow. 1. Effect of tablet geometry in buffered medium. J Pharm Sci 85 313-319, 1996. 

GD Leesman, PJ Sinko, GL Amidon. Simulation of oral drug absorption Gastric emptying and gastrointestinal motility. In PG Welling, FLS Tse, eds. Pharmacokinetics. 2nd ed. New York Marcel Dekker, 1989, pp 267-284. 

Only a subset of the parameter values in the O Flaherfy model require inputs from the user to simulate blood and tissue lead concentrations. Lead-related parameters for which values can be entered into the model include fractional absorption from the gastrointestinal tract partition coefficients for lead in nonbone tissues and in the surface region of bone maximum capacity and half-saturation concentration for capacity-limited binding in the erythrocyte elimination clearance fractional clearance of lead from plasma into forming bone and the restricted permeability coefficients for lead diffusion within bone, from plasma into bone, and from bone into plasma (O Flaherty 1991a). 

The second situation when IVIVC is not likely for class II drugs is where the absorption is limited by the saturation solubility in the gastrointestinal tract rather than the dissolution rate, as discussed in more detail above. In this situation, the drug concentration in the gastrointestinal tract will be close to the saturation solubility, and changes of the dissolution rate will not affect the plasma concentrationtime profile and in vivo bioavailability. Standard in vitro dissolution tests are carried out under sink conditions , i.e., at concentrations well below the saturation solubility. Thus, only effects related to dissolution rate can be predicted in vitro. If more physiologically relevant dissolution media are used, which do not necessarily provide sink conditions , the possibility for IVIVC could be improved, as has been indicated by the results of recent studies using simulated intestinal medium [76],... 

An acute intravenous study can provide accurate rates of metabolism without interference from intestinal flora, plus rates of renal and biliary elimination, if urine and bile are collected. This route also avoids the variability in delivered dose associated with oral absorption and ensures that the maximum amount of radiolabel is excreted in the urine or bile for purposes of detection. Once IV data and parameters are available, they can be used with plasma concentrations from limited oral studies to compute intestinal absorption via the ratio of Areas Under the (plasma and/or urine) Curves or via simulations of absorption with gastrointestinal absorption models. 

Kalantzi L, Ftirst T, Abrahamsson B, Goumas K, Kalioras V, Dressman J, Reppas C. Characterization of the human upper gastrointestinal contents under conditions simulating bioavailability studies in the fasting and fed states. Proceedings of the AAPS Annual Meeting, Salt Lake City, UT, 2003. 

The direct transport of absorbed drugs into systemic circulation, effectively by-passing the first-pass effect of the liver and gastrointestinal tract Lower enzymatic activity compared to the gastrointestinal tract or liver Amenability to self-medication, which increases patient compliance Possibility of pulsatile delivery of some drugs to simulate the biorhythmic release of these drugs Lower risk of overdosage Achievement of controlled release... 

Lomstein Pedersen B, Mullertz A, Brondstedt H, Gjelstrup Kristensen H (2000) A comparison of the solubility of danazol in human and simulated gastrointestinal fluids. Pharm. Res. 17 891-894. 

WillmanS, Schmitt W, Keldenich J, Dressman JB (2003) A physiologic model for simulating gastrointestinal flow and drug absorption in rats. Pharm. Res. 20 1766— 1771. 

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