Prediction of the Contribution Ratio of a Target Metabolic Enzyme to Clearance from Chemical Structure Information

Mol Pharm. 2023 Jan 2;20(1):419-426. doi: 10.1021/acs.molpharmaceut.2c00698. Epub 2022 Dec 20.


The contribution ratio of metabolic enzymes such as cytochrome P450 to in vivo clearance (fraction metabolized: fm) is a pharmacokinetic index that is particularly important for the quantitative evaluation of drug-drug interactions. Since obtaining experimental in vivo fm values is challenging, those derived from in vitro experiments have often been used alternatively. This study aimed to explore the possibility of constructing machine learning models for predicting in vivo fm using chemical structure information alone. We collected in vivo fm values and chemical structures of 319 compounds from a public database with careful manual curation and constructed predictive models using several machine learning methods. The results showed that in vivo fm values can be obtained from structural information alone with a performance comparable to that based on in vitro experimental values and that the prediction accuracy for the compounds involved in CYP induction or inhibition is significantly higher than that by using in vitro values. Our new approach to predicting in vivo fm values in the early stages of drug discovery should help improve the efficiency of the drug optimization process.

Keywords: CYP3A4; drug−drug interaction; fm; in silico prediction; pharmacokinetics.

MeSH terms

  • Area Under Curve
  • Cytochrome P-450 CYP3A* / metabolism
  • Cytochrome P-450 Enzyme System* / metabolism
  • Drug Discovery / methods
  • Drug Interactions


  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System