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Related Experiment Videos

High throughput microsomal stability assay for insoluble compounds.

Li Di1, Edward H Kerns, Susan Q Li

  • 1Wyeth Research, P.O. Box CN 8000, Princeton, NJ 08543-8000, USA. DIL@WYETH.COM

International Journal of Pharmaceutics
|April 20, 2006
PubMed
Summary

Drug discovery compounds with poor solubility can yield artificially high metabolic stability results using the aqueous dilution method. The cosolvent method offers a more reliable approach for assessing metabolic stability in drug discovery.

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Area of Science:

  • Medicinal Chemistry
  • Pharmacology
  • Drug Discovery

Background:

  • High-throughput metabolic stability assays are crucial in drug discovery for compound optimization and preclinical assessment.
  • Standard assay validation often uses commercial drugs, which may not represent the properties of novel drug discovery compounds, such as high lipophilicity and low solubility.

Purpose of the Study:

  • To investigate the impact of very low aqueous solubility on the results of metabolic stability assays.
  • To compare the suitability of the aqueous dilution method versus the cosolvent method for assessing metabolic stability of diverse drug discovery compounds.

Main Methods:

  • Comparison of two metabolic stability assay methodologies: the aqueous dilution method and the cosolvent method.
  • Evaluation of assay performance using commercial drugs and representative drug discovery compounds, including those with poor solubility.

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Main Results:

  • Both methods yielded comparable metabolic stability results for compounds with typical drug-like properties.
  • The aqueous dilution method produced artificially inflated metabolic stability values for highly lipophilic, insoluble drug discovery compounds.
  • The cosolvent method demonstrated greater applicability by minimizing precipitation and non-specific binding for poorly soluble compounds.

Conclusions:

  • The choice of metabolic stability assay method is critical, particularly for drug discovery compounds with limited solubility.
  • The cosolvent method is more appropriate for accurately assessing the metabolic stability of compounds encountered during drug discovery due to its ability to handle poor solubility.
  • Findings highlight the need for method selection based on compound physicochemical properties to ensure reliable in vitro-in vivo correlation.