Absorption Caco2 - Revision history

Kirilas: Updated for 2020 release

2020-08-18T09:51:02Z

Updated for 2020 release

Kirilas at 07:43, 20 June 2017

2017-06-20T07:43:38Z

← Older revision		Revision as of 07:43, 20 June 2017
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	</li>		</li>
	<li>Experimental conditions used in simulation. Type in new values to change the pH or stirring rate (rpm)</li>		<li>Experimental conditions used in simulation. Type in new values to change the pH or stirring rate (rpm)</li>
	<li>Estimated value of Caco-2 permeability (P<sub>e</sub>, cm/s) and the relative contributions of transcellular and paracellular pathways, calculated as a function of compound structure and provided parameters<br>[[File:Absorption_caco2_results.png\|400px]]</li>		<li><span id="Caco2_value">Estimated value of Caco-2 permeability (P<sub>e</sub>, cm/s) and the relative contributions of transcellular and paracellular pathways, calculated as a function of compound structure and provided parameters</span><br>[[File:Absorption_caco2_results.png\|400px]]</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>

Kirilas at 10:07, 15 June 2017

2017-06-15T10:07:40Z

← Older revision		Revision as of 10:07, 15 June 2017
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	<div class="mw-collapsible ~~mw-collapsed~~">		<div class="mw-collapsible">

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

Kirilas: /* Calculated quantitative parameters */

2013-02-15T09:21:45Z

Calculated quantitative parameters

← Older revision		Revision as of 09:21, 15 February 2013
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	===Calculated quantitative parameters===		===Calculated quantitative parameters===
	<br />		<br />
	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 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).

	===Descriptors & Modeling Method===		===Descriptors & Modeling Method===
	<br />		<br />

Kirilas: /* Transport mechanisms */

2013-02-15T09:21:23Z

Transport mechanisms

← Older revision		Revision as of 09:21, 15 February 2013
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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.
	</div>		</div>
	</div>		</div>

Kirilas: /* Reference database */

2013-02-15T09:20:58Z

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.		In addition to HIA and Caco-2 permeability predictions, ACD/Percepta provides Absorption DB - a 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 />		<br />

Kirilas: /* Interface */

2012-05-25T07:39:32Z

Interface

← Older revision		Revision as of 07:39, 25 May 2012
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	<ol>		<ol>
	<li>Calculated ~~logP~~, number of H-~~Bond~~ donors and McGowan volume. Click and type a new value to model the limiting effect of lipophilicity, ~~H-Bonding~~ acidity and molecular size on Caco-2 permeability</li>		<li>Calculated LogP, number of H-bond donors and McGowan volume. Click and type a new value to model the limiting effect of lipophilicity, hydrogen bonding acidity and molecular size on Caco-2 permeability</li>
	<li>Calculated acid and base ionization constants. [[File:Absorption_Caco2_Simulation.png\|right]] Click to select or type new pKa(acid) and pKa(base) values to model the limiting effect of ionization constants on Caco-2 permeability.		<li>Calculated acid and base ionization constants. [[File:Absorption_Caco2_Simulation.png\|right]] Click to select or type new pKa(acid) and pKa(base) values to model the limiting effect of ionization constants on Caco-2 permeability.

	:a. Click to reverse to an automatically calculated property value (~~logP~~ in this picture) for a compound and to recalculate the Caco-2 permeability		:a. Click to reverse to an automatically calculated property value (LogP in this picture) for a compound and to recalculate the Caco-2 permeability

	:b. Click to recalculate the Caco-2 permeability using the currently specified parameter values		:b. Click to recalculate the Caco-2 permeability using the currently specified parameter values

Kirilas: /* Features */

2012-05-25T07:37:53Z

Features

← Older revision		Revision as of 07:37, 25 May 2012
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	===Features===		===Features===
	* Calculates the extent of passive permeability of analyzed compounds across ~~jejunal epithelium and~~ Caco-2 cell monolayers using values ~~of their physicochemical properties~~ such as lipophilicity (LogP) and ionization (pKa) as inputs.		* Calculates the extent of passive permeability of analyzed compounds across Caco-2 cell monolayers at specified pH and stirring conditions using physicochemical property values such as lipophilicity (LogP) and ionization (pKa) as inputs.
	* Gives an estimate of relative contributions of different transport routes ~~for~~ Caco-2 permeability ~~predictions~~.		* Gives an estimate of relative contributions of different transport routes to Caco-2 permeability.
	* Allows entering experimentally measured physicochemical properties instead of automatically calculated values to improve the quality of predictions. ~~In case of Caco-2 permeability predictor~~ experimental conditions (pH and stirring rate) may also be ~~entered~~ manually for full flexibility of the simulation.		* Allows entering experimentally measured physicochemical properties instead of automatically calculated values to improve the quality of predictions. The experimental conditions (pH and stirring rate) may also be adjusted manually for full flexibility of the simulation.
	* Entering user-defined LogP and pKa values allows the researcher to model the limiting effect of lipophilicity and ionization on intestinal permeation rate, thus providing a straightforward route for property-based design of oral drugs.		* Entering user-defined LogP and pKa values allows the researcher to model the limiting effect of lipophilicity and ionization on intestinal permeation rate, thus providing a straightforward route for property-based design of oral drugs.
	* 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 the training set along with each Caco-2 permeability prediction.<br />
	* Displays the experimental values of the relevant properties for up to 3 similar structures from ~~Absorption DB~~ along with each Caco-2 permeability prediction.<br />


	==Interface==		==Interface==

Kristina: /* Interface */

2012-05-14T08:00:12Z

Interface

← Older revision		Revision as of 08:00, 14 May 2012
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	</li>		</li>
	<li>Experimental conditions used in simulation. Type in new values to change the pH or stirring rate (rpm)</li>		<li>Experimental conditions used in simulation. Type in new values to change the pH or stirring rate (rpm)</li>
	<li>Estimated value of Caco-2 permeability (P<sub>e</sub>, cm/s) and the relative contributions of transcellular and paracellular pathways, calculated as a function of compound structure and provided parameters<br>[[File:Absorption_caco2_results.png]]</li>		<li>Estimated value of Caco-2 permeability (P<sub>e</sub>, cm/s) and the relative contributions of transcellular and paracellular pathways, calculated as a function of compound structure and provided parameters<br>[[File:Absorption_caco2_results.png\|400px]]</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>
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	<div class="mw-collapsible mw-collapsed">		<div class="mw-collapsible mw-collapsed">

	==Technical information==		==Technical information==
	<br />		<br />

Kristina at 07:57, 14 May 2012

2012-05-14T07:57:59Z

← Older revision		Revision as of 07:57, 14 May 2012
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	==Overview==		==Overview==
	<br />		<br />
			Intestinal permeability of drugs together with solubility are the two key factors affecting their oral bioavailability. 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.<br>
			Caco-2 module contains a mechanistic predictive model of compound permeability across Caco-2 cell monolayer at different experimental conditions. The predictive algorithm was developed using data from >800 experiments with nearly 600 compounds. The resulting model is ionization-specific and also takes into account permeabilities via transcellular and paracellular routes. It uses essential physicochemical properties such as lipophilicity, ionization constants, number of H-Bond donors and molecular size (calculated or experimental if available) as inputs.<br />

	Intestinal permeability of drugs together with solubility are the two key factors affecting their oral bioavailability. 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.
	Caco-2 module contains a mechanistic predictive model of compound permeability across Caco-2 cell monolayer at different experimental conditions. The predictive algorithm was developed using data from >800 experiments with nearly 600 compounds. The resulting model is ionization-specific and also takes into account permeabilities via transcellular and paracellular routes. It uses essential physicochemical properties such as lipophilicity, ionization constants, number of H-Bond donors and molecular size (calculated or experimental if available) as inputs.<br />

	===Features===		===Features===
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	* Entering user-defined LogP and pKa values allows the researcher to model the limiting effect of lipophilicity and ionization on intestinal permeation rate, thus providing a straightforward route for property-based design of oral drugs.		* Entering user-defined LogP and pKa values allows the researcher to model the limiting effect of lipophilicity and ionization on intestinal permeation rate, thus providing a straightforward route for property-based design of oral drugs.
	* 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.		* Displays the experimental values of the relevant properties for up to 3 similar structures from Absorption DB along with each Caco-2 permeability prediction.<br />


	==Interface==		==Interface==
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	<ol>		<ol>
	<li>Calculated logP, number of H-Bond donors and McGowan volume. Click and type a new value to model the limiting effect of lipophilicity, H-Bonding acidity and molecular size on Caco-2 permeability</li>		<li>Calculated logP, number of H-Bond donors and McGowan volume. Click and type a new value to model the limiting effect of lipophilicity, H-Bonding acidity and molecular size on Caco-2 permeability</li>
	<li>Calculated acid and base ionization constants. [[~~Image~~:Absorption_Caco2_Simulation.png\|right]] Click to select or type new pKa(acid) and pKa(base) values to model the limiting effect of ionization constants on Caco-2 permeability.		<li>Calculated acid and base ionization constants. [[File:Absorption_Caco2_Simulation.png\|right]] Click to select or type new pKa(acid) and pKa(base) values to model the limiting effect of ionization constants on Caco-2 permeability.

	:a. Click to reverse to an automatically calculated property value (logP in this picture) for a compound and to recalculate the Caco-2 permeability		:a. Click to reverse to an automatically calculated property value (logP in this picture) for a compound and to recalculate the Caco-2 permeability
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	</li>		</li>
	<li>Experimental conditions used in simulation. Type in new values to change the pH or stirring rate (rpm)</li>		<li>Experimental conditions used in simulation. Type in new values to change the pH or stirring rate (rpm)</li>
	<li>Estimated value of Caco-2 permeability (Pe, cm/s) and the relative contributions of transcellular and paracellular pathways, calculated as a function of compound structure and provided parameters<br>[[File:Absorption_caco2_results.png]]</li>		<li>Estimated value of Caco-2 permeability (P<sub>e</sub>, cm/s) and the relative contributions of transcellular and paracellular pathways, calculated as a function of compound structure and provided parameters<br>[[File:Absorption_caco2_results.png]]</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>