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Computational prediction of drug solubility in fasted simulated and aspirated human intestinal fluid.

Fagerberg JH, Karlsson E, Ulander J, Hanisch G, Bergström CA - Pharm. Res. (2014)

Bottom Line: Modest relationships between Sapp in PhBpH6.5 and FaSSIF (R(2) = 0.61) or HIF (R(2) = 0.62) were found.Accuracy improved when solubility in PhBpH6.5 was added as a descriptor (FaSSIF, R(2) = 0.76 and RMSETe of 0.65; HIF, R(2) = 0.86 and RMSETe of 0.69), whereas no improvement was seen when melting point (Tm) or logDpH 6.5 were included in the models.If experimentally determined pH-dependent solubility values were available, this further improved the accuracy of the predictions.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy, Uppsala University, Biomedical Centre, P.O. Box 580, SE-751 23, Uppsala, Sweden.

ABSTRACT

Purpose: To develop predictive models of apparent solubility (Sapp) of lipophilic drugs in fasted state simulated intestinal fluid (FaSSIF) and aspirated human intestinal fluid (HIF).

Methods: Measured Sapp values in FaSSIF, HIF and phosphate buffer pH 6.5 (PhBpH6.5) for 86 lipophilic drugs were compiled and divided into training (Tr) and test (Te) sets. Projection to latent structure (PLS) models were developed through variable selection of calculated molecular descriptors. Experimentally determined properties were included to investigate their contribution to the predictions.

Results: Modest relationships between Sapp in PhBpH6.5 and FaSSIF (R(2) = 0.61) or HIF (R(2) = 0.62) were found. As expected, there was a stronger correlation obtained between FaSSIF and HIF (R(2) = 0.78). Computational models were developed using calculated descriptors alone (FaSSIF, R(2) = 0.69 and RMSEte of 0.77; HIF, R(2) = 0.84 and RMSEte of 0.81). Accuracy improved when solubility in PhBpH6.5 was added as a descriptor (FaSSIF, R(2) = 0.76 and RMSETe of 0.65; HIF, R(2) = 0.86 and RMSETe of 0.69), whereas no improvement was seen when melting point (Tm) or logDpH 6.5 were included in the models.

Conclusion: Computational models were developed, that reliably predicted Sapp of lipophilic compounds in intestinal fluid, from molecular structures alone. If experimentally determined pH-dependent solubility values were available, this further improved the accuracy of the predictions.

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Related in: MedlinePlus

Consensus model for compounds with residuals over 1 log10 unit in any model based on calculated descriptors. Light green circles without outline show the worst prediction from either the ANN or PLS model. Outlined dark turquoise circles represent the consensus model prediction.
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Fig6: Consensus model for compounds with residuals over 1 log10 unit in any model based on calculated descriptors. Light green circles without outline show the worst prediction from either the ANN or PLS model. Outlined dark turquoise circles represent the consensus model prediction.

Mentions: The consensus model based on the calculations obtained from our FaSSIF model and the ADMET Predictor results exhibited a lower RMSEte (0.70) compared to each of the models separately (Table III). The PLS model was however more accurate compared to the consensus model in the prediction of the solubility of the discovery test set. Importantly, predictions of outliers resulting from each of the PLS and ANN models were greatly improved by consensus modelling (Fig. 6).Table III


Computational prediction of drug solubility in fasted simulated and aspirated human intestinal fluid.

Fagerberg JH, Karlsson E, Ulander J, Hanisch G, Bergström CA - Pharm. Res. (2014)

Consensus model for compounds with residuals over 1 log10 unit in any model based on calculated descriptors. Light green circles without outline show the worst prediction from either the ANN or PLS model. Outlined dark turquoise circles represent the consensus model prediction.
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4300419&req=5

Fig6: Consensus model for compounds with residuals over 1 log10 unit in any model based on calculated descriptors. Light green circles without outline show the worst prediction from either the ANN or PLS model. Outlined dark turquoise circles represent the consensus model prediction.
Mentions: The consensus model based on the calculations obtained from our FaSSIF model and the ADMET Predictor results exhibited a lower RMSEte (0.70) compared to each of the models separately (Table III). The PLS model was however more accurate compared to the consensus model in the prediction of the solubility of the discovery test set. Importantly, predictions of outliers resulting from each of the PLS and ANN models were greatly improved by consensus modelling (Fig. 6).Table III

Bottom Line: Modest relationships between Sapp in PhBpH6.5 and FaSSIF (R(2) = 0.61) or HIF (R(2) = 0.62) were found.Accuracy improved when solubility in PhBpH6.5 was added as a descriptor (FaSSIF, R(2) = 0.76 and RMSETe of 0.65; HIF, R(2) = 0.86 and RMSETe of 0.69), whereas no improvement was seen when melting point (Tm) or logDpH 6.5 were included in the models.If experimentally determined pH-dependent solubility values were available, this further improved the accuracy of the predictions.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy, Uppsala University, Biomedical Centre, P.O. Box 580, SE-751 23, Uppsala, Sweden.

ABSTRACT

Purpose: To develop predictive models of apparent solubility (Sapp) of lipophilic drugs in fasted state simulated intestinal fluid (FaSSIF) and aspirated human intestinal fluid (HIF).

Methods: Measured Sapp values in FaSSIF, HIF and phosphate buffer pH 6.5 (PhBpH6.5) for 86 lipophilic drugs were compiled and divided into training (Tr) and test (Te) sets. Projection to latent structure (PLS) models were developed through variable selection of calculated molecular descriptors. Experimentally determined properties were included to investigate their contribution to the predictions.

Results: Modest relationships between Sapp in PhBpH6.5 and FaSSIF (R(2) = 0.61) or HIF (R(2) = 0.62) were found. As expected, there was a stronger correlation obtained between FaSSIF and HIF (R(2) = 0.78). Computational models were developed using calculated descriptors alone (FaSSIF, R(2) = 0.69 and RMSEte of 0.77; HIF, R(2) = 0.84 and RMSEte of 0.81). Accuracy improved when solubility in PhBpH6.5 was added as a descriptor (FaSSIF, R(2) = 0.76 and RMSETe of 0.65; HIF, R(2) = 0.86 and RMSETe of 0.69), whereas no improvement was seen when melting point (Tm) or logDpH 6.5 were included in the models.

Conclusion: Computational models were developed, that reliably predicted Sapp of lipophilic compounds in intestinal fluid, from molecular structures alone. If experimentally determined pH-dependent solubility values were available, this further improved the accuracy of the predictions.

Show MeSH
Related in: MedlinePlus