Prediction of drug tissue to plasma concentration ratios using a measured volume of distribution in combination with lipophilicity

J Pharm Sci. 2008 Jun;97(6):2324-39. doi: 10.1002/jps.21130.

Abstract

One of the drug specific parameters needed in physiologically based pharmacokinetic (PBPK) models is the tissue to plasma drug concentration ratios (K(p) values). The aim of this study was to develop an empirical method for predicting K(p) values using a preclinically determined in vivo volume of distribution, in combination with descriptors for drug lipophilicity. Pharmacokinetic data in laboratory animals for a wide range of drug compounds were collected. Obtained correlations between K(p) values for muscle and other tissues, in a training set of 49 compounds, were used to predict K(p) values for a test set of 22 compounds, based on their volume of distribution and lipophilicity. Predicted K(p) values agreed well with experimentally determined values (n = 118), especially for noneliminating tissues (r(2) = 0.81) with 72% and 87% being within a factor +/-2 and +/-3, respectively. In conclusion, we present an empirical method based on a measured volume of distribution and a drug lipophilicity descriptor, which can be used to predict tissue K(p) values with reasonable accuracy.

MeSH terms

  • Adipose Tissue / metabolism
  • Animals
  • Haplorhini
  • Mice
  • Models, Biological*
  • Molecular Structure
  • Muscles / metabolism
  • Pharmaceutical Preparations / blood
  • Pharmaceutical Preparations / chemistry
  • Pharmaceutical Preparations / metabolism*
  • Pharmacokinetics*
  • Rabbits
  • Rats
  • Reproducibility of Results
  • Structure-Activity Relationship
  • Tissue Distribution

Substances

  • Pharmaceutical Preparations