Absorption - Revision history

Kirilas: /* Technical information */

2020-08-20T08:07:49Z

Technical information

Kirilas at 10:07, 15 June 2017

2017-06-15T10:07:27Z

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	==Technical information==		==Technical information==

Kirilas: /* Transport mechanisms */

2013-02-15T09:22:47Z

Transport mechanisms

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	===Transport mechanisms===		===Transport mechanisms===
	The predictive models comprising the Absorption module account for '''passive''' transport of analyzed compounds across intestinal barrier. In order to propose a clear physicochemical explanation of passive diffusion process, the data used for model development (both %HIA and Caco-2 permeability sets containing about 600 data points) were thoroughly evaluated to exclude values affected by enzymatic efflux or influx. For such compounds special alerts are displayed in the Bioavailability module indicating that expected oral bioavailability/absorption values for these molecules may be higher or lower due to presence of carrier-mediated processes.		The predictive models comprising the Passive Absorption module account for '''passive''' transport of analyzed compounds across intestinal barrier. In order to propose a clear physicochemical explanation of passive diffusion process, the data used for model development (both %HIA and Caco-2 permeability sets containing about 600 data points) were thoroughly evaluated to exclude values affected by enzymatic efflux or influx. For such compounds special alerts are displayed in the Oral Bioavailability module indicating that expected oral bioavailability/absorption values for these molecules may be higher or lower due to presence of carrier-mediated processes.
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Kirilas: /* Reference database */

2013-02-15T09:20:17Z

Reference database

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	===Reference database===		===Reference database===
	In addition to HIA and Caco-2 permeability predictions, ACD/Percepta provides Absorption DB - a browsable database of human intestinal absorption & bioavailability. The experimental data were compiled from reference pharmacokinetic tabulations and original articles, the main sources being "Therapeutic Drugs" (ed. by C. ~~dollery~~), Goodman & Gilman's "The Pharmacological Basis of Therapeutics", and a compilation by Zhao, Y. H. et al. ''J Pharm Sci.'' '''2001''';90(6):749-84. A qualitative assignment of absorption category (good, moderate, poor) is provided for each compound in the database along with comments regarding the quantitative extent of absorption/bioavailability, presence of carrier-mediated transport, etc. where available.<br />		In addition to HIA and Caco-2 permeability predictions, ACD/Percepta provides Absorption DB - a browsable database of human intestinal absorption & bioavailability. The experimental data were compiled from reference pharmacokinetic tabulations and original articles, the main sources being "Therapeutic Drugs" (ed. by C. Dollery), Goodman & Gilman's "The Pharmacological Basis of Therapeutics", and a compilation by Zhao, Y. H. et al. ''J Pharm Sci.'' '''2001''';90(6):749-84. A qualitative assignment of absorption category (good, moderate, poor) is provided for each compound in the database along with comments regarding the quantitative extent of absorption/bioavailability, presence of carrier-mediated transport, etc. where available.<br />

	===Transport mechanisms===		===Transport mechanisms===

Kirilas: /* Reference database */

2013-02-15T09:20:02Z

Reference database

← Older revision		Revision as of 09:20, 15 February 2013
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	===Reference database===		===Reference database===
	~~Absorption\~~Absorption DB ~~module contains~~ a browsable database of human intestinal absorption & bioavailability. The experimental data were compiled from reference pharmacokinetic tabulations and original articles, the main sources being "Therapeutic Drugs" (ed. by C. dollery), Goodman & Gilman's "The Pharmacological Basis of Therapeutics", and a compilation by Zhao, Y. H. et al. ''J Pharm Sci.'' '''2001''';90(6):749-84. A qualitative assignment of absorption category (good, moderate, poor) is provided for each compound in the database along with comments regarding the quantitative extent of absorption/bioavailability, presence of carrier-mediated transport, etc. where available.<br />		In addition to HIA and Caco-2 permeability predictions, ACD/Percepta provides Absorption DB - a browsable database of human intestinal absorption & bioavailability. The experimental data were compiled from reference pharmacokinetic tabulations and original articles, the main sources being "Therapeutic Drugs" (ed. by C. dollery), Goodman & Gilman's "The Pharmacological Basis of Therapeutics", and a compilation by Zhao, Y. H. et al. ''J Pharm Sci.'' '''2001''';90(6):749-84. A qualitative assignment of absorption category (good, moderate, poor) is provided for each compound in the database along with comments regarding the quantitative extent of absorption/bioavailability, presence of carrier-mediated transport, etc. where available.<br />


	===Transport mechanisms===		===Transport mechanisms===

Kirilas: /* Calculated quantitative parameters */

2013-02-15T09:18:03Z

Calculated quantitative parameters

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	===Calculated quantitative parameters===		===Calculated quantitative parameters===
	The main output of the Absorption module is the maximum achievable extent of human intestinal absorption (when solubility is not a limiting factor) expressed as a percentage value and denoted %HIA. Typically, compounds exhibiting %HIA > 70% are considered well absorbed, those with %HIA < 30% - poorly absorbed, while values in the range 30 - 70% represent moderate absorption. Intestinal permeability rates corresponding to the respective %HIA values are calibrated on several scales and given as:		The main output of the Passive Absorption module is the maximum achievable extent of human intestinal absorption (when solubility is not a limiting factor) expressed as a percentage value and denoted %HIA. Typically, compounds exhibiting %HIA > 70% are considered well absorbed, those with %HIA < 30% - poorly absorbed, while values in the range 30 - 70% represent moderate absorption. Intestinal permeability rates corresponding to the respective %HIA values are calibrated on several scales and given as:

	* Effective jejunal permeability coefficients at pH 6.5 (''P<sub>e</sub>'', 10<sup>-4</sup> cm/s)		* Effective jejunal permeability coefficients at pH 6.5 (''P<sub>e</sub>'', 10<sup>-4</sup> cm/s)
	* Absorption rate constants (''k<sub>a</sub>'', min<sup>-1</sup>).		* Absorption rate constants (''k<sub>a</sub>'', min<sup>-1</sup>).

	Additionally, Absorption\Caco-2 module ~~presents~~ effective permeability coefficients in Caco-2 monolayers (''P<sub>e</sub>'', 10<sup>-6</sup> cm/s) at user-defined conditions (pH and stirring rate).		Additionally, Passive Absorption\Caco-2 module predicts effective permeability coefficients in Caco-2 monolayers (''P<sub>e</sub>'', 10<sup>-6</sup> cm/s) at user-defined conditions (pH and stirring rate).

	===Descriptors & Modeling Method===		===Descriptors & Modeling Method===
	Descriptors used for modeling included key physicochemical properties - octanol/water LogP of neutral species as a determinant of lipophilicity, ion form fractions at pH 6.5 calculated from the respective pKa values, number of hydrogen bond donors in the molecule, and McGowan characetristic volume reflecting molecular size. All physicochemical parameter values were calculated with Algorithm Builder 1.8.		Descriptors used for modeling included key physicochemical properties - octanol/water LogP of neutral species as a determinant of lipophilicity, ion form fractions at pH 6.5 calculated from the respective pKa values, number of hydrogen bond donors in the molecule, and McGowan characetristic volume reflecting molecular size. All physicochemical parameter values were calculated with Algorithm Builder 1.8.

Kirilas: /* Technical information */

2013-01-31T10:56:00Z

Technical information

← Older revision		Revision as of 10:56, 31 January 2013
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	Only a short summary of main technical aspects of Absorption predictor is given here. For a more detailed description of the modeling approach and underlying theory please refer to Reynolds, D. P., et al. ''J Pharm Sci.'' '''2009'''; ~~In press~~. [http://www3.interscience.wiley.com/journal/122309349/abstract]<br />		Only a short summary of main technical aspects of Absorption predictor is given here. For a more detailed description of the modeling approach and underlying theory please refer to Reynolds, D. P., et al. ''J Pharm Sci.'' '''2009''';98(11):4039–54. [http://www3.interscience.wiley.com/journal/122309349/abstract]<br />

	===Calculated quantitative parameters===		===Calculated quantitative parameters===

Kristina at 13:23, 29 May 2012

2012-05-29T13:23:24Z

← Older revision		Revision as of 13:23, 29 May 2012
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	* Provides access to Absorption DB – a fully browsable and searchable database containing experimental data that was used for the development of HIA model together with corresponding literature references.		* Provides access to Absorption DB – a fully browsable and searchable database containing experimental data that was used for the development of HIA model together with corresponding literature references.
	* Displays the experimental values of the relevant properties for up to 3 similar structures from Absorption DB along with each HIA prediction.<br />		* Displays the experimental values of the relevant properties for up to 3 similar structures from Absorption DB along with each HIA prediction.<br />
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	== Interface ==		== Interface ==

Kristina at 13:22, 29 May 2012

2012-05-29T13:22:46Z

← Older revision		Revision as of 13:22, 29 May 2012
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	==Overview==		==Overview==

	Human intestinal Absorption (HIA) of drugs together with solubility are the two key factors affecting their oral bioavailability. HIA may be defined as a drug passing from the lumen into the tissue of the gastrointestinal tract [http://www.ncbi.nlm.nih.gov/pubmed/2654032?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum]. Once in the tissue, the drug is considered absorbed. Absorption predictor in [[ACD/Percepta]] analyzes HIA in terms of passive permeability that is not affected by any side processes such as limited solubility/dissolution, variable oral dose, chemical stability, active transport, and 1st pass metabolism in gut or liver.<br>		Human intestinal Absorption (HIA) of drugs together with solubility are the two key factors affecting their oral bioavailability. HIA may be defined as a drug passing from the lumen into the tissue of the gastrointestinal tract [http://www.ncbi.nlm.nih.gov/pubmed/2654032?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum]. Once in the tissue, the drug is considered absorbed. Absorption predictor in ACD/Percepta analyzes HIA in terms of passive permeability that is not affected by any side processes such as limited solubility/dissolution, variable oral dose, chemical stability, active transport, and 1st pass metabolism in gut or liver.<br>
	Absorption module provides accurate predictions of passive intestinal permeability (on jejunal and Caco-2 scales) and extent of oral absorption (%HIA) of drug candidates. These predictions based on intuitive, easily interpretable physicochemical models enable the researchers to rank and select lead compounds according to their permeability across intestinal barrier and to exclude candidates exhibiting extremely poor absorption at the earliest stages.		Absorption module provides accurate predictions of passive intestinal permeability (on jejunal and Caco-2 scales) and extent of oral absorption (%HIA) of drug candidates. These predictions based on intuitive, easily interpretable physicochemical models enable the researchers to rank and select lead compounds according to their permeability across intestinal barrier and to exclude candidates exhibiting extremely poor absorption at the earliest stages.

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	</li>		</li>
	<li>Quantitative estimate of maximum intestinal passive absorption of a compound and the relative contributions from the transcellular and paracellular routes of absorption, calculated as a function of compound structure, lipophilicity and ionization constants<br>[[File:~~absorption_hia_results~~.png\|400px]]</li>		<li>Quantitative estimate of maximum intestinal passive absorption of a compound and the relative contributions from the transcellular and paracellular routes of absorption, calculated as a function of compound structure, lipophilicity and ionization constants<br>[[File:Absorption_hia_results.png\|400px]]</li>
	<li>Estimated human jejunal permeability (Pe), in cm/s, and calculated intestinal absorption rate constant (k<sub>a</sub>) in units of 1/min</li>		<li>Estimated human jejunal permeability (Pe), in cm/s, and calculated intestinal absorption rate constant (k<sub>a</sub>) in units of 1/min</li>
	<li>Up to 3 most similar structures in the '''Absorption DB''' with experimental values and references</li>		<li>Up to 3 most similar structures in the '''Absorption DB''' with experimental values and references</li>

Kirilas: /* Interface */

2012-05-25T07:34:10Z

Interface

← Older revision		Revision as of 07:34, 25 May 2012
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	</li>		</li>
	<li>Quantitative estimate of maximum intestinal passive absorption of a compound and the relative contributions from the transcellular and paracellular routes of absorption, calculated as a function of compound structure, lipophilicity and ionization constants<br>[[File:absorption_hia_results.png\|400px]]</li>		<li>Quantitative estimate of maximum intestinal passive absorption of a compound and the relative contributions from the transcellular and paracellular routes of absorption, calculated as a function of compound structure, lipophilicity and ionization constants<br>[[File:absorption_hia_results.png\|400px]]</li>
	<li>Estimated human ~~jejunum~~ permeability, in cm/s, and calculated intestinal ~~passive~~ absorption rate in units of 1/min</li>		<li>Estimated human jejunal permeability (Pe), in cm/s, and calculated intestinal absorption rate constant (k<sub>a</sub>) in units of 1/min</li>
	<li>Up to 3 most similar structures in the '''Absorption DB''' with experimental values and references</li>		<li>Up to 3 most similar structures in the '''Absorption DB''' with experimental values and references</li>
	</ol>		</ol>