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Predicting unbound drug fraction (fu_inc) for in vitro clearance (CL_int) requires more than simple lipophilicity. Equilibrium dialysis can be used indirectly, but direct measurement may fail for highly bound drugs.

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Area of Science:

  • Pharmacokinetics
  • Drug Metabolism
  • Computational Chemistry

Background:

  • Accurate prediction of drug clearance is crucial for drug development.
  • The unbound drug fraction (fu_inc) in vitro is a key parameter for predicting in vivo clearance.
  • Current methods often rely on lipophilicity, but its predictive power for fu_inc is questionable.

Purpose of the Study:

  • To evaluate the reliability of equilibrium dialysis for measuring fu_inc.
  • To assess the predictive capability of lipophilicity (logD7.4) for fu_inc.
  • To identify limitations in current fu_inc prediction methods.

Main Methods:

  • Measured fu_inc using equilibrium dialysis and direct methods with human liver microsomes and rat hepatocytes.
  • Utilized a diverse set of compounds across a wide lipophilicity range (logD7.4).
  • Compared fu_inc values obtained from different methods and correlated them with lipophilicity.

Main Results:

  • Equilibrium dialysis showed good agreement with direct measurements for compounds with logD7.4 < 3.5.
  • Agreement significantly worsened for compounds with logD7.4 > 3.5.
  • Direct measurement methods appear to underestimate fu_inc for highly bound drugs.

Conclusions:

  • Unbound intrinsic clearance (CL_int) can be calculated indirectly using equilibrium dialysis data.
  • Simple lipophilicity measures alone are insufficient for accurately predicting fu_inc, especially for highly lipophilic or bound compounds.
  • Further development of predictive algorithms incorporating more parameters is needed.