Development of a novel method for predicting human volume of distribution at steady-state of basic drugs and comparative assessment with existing methods

J Pharm Sci. 2009 Dec;98(12):4941-61. doi: 10.1002/jps.21759.


The parameters characterizing tissue distribution refer to the tissue/plasma partition coefficients (Kp), which can be used to derive volume of distribution at steady-state (V(ss)). The effort for predicting drug distribution in human has been further expanded to calculation methods using in vitro-based algorithms. The objective of the present study was to develop a novel prediction method to estimate human V(ss) for moderate-to-strong bases. The predictive performance of the novel method was compared with other well established in vitro-based methods available in the literature. Relevant information collected from previous prediction studies of V(ss) facilitated the development of the novel method. This was based on the calculation of V(ss) from data on Kp, which were estimated by correlating the unbound tissue/plasma ratio in vivo (Kpu) with the unbound red blood cells partitioning (RBCu) determined in vitro. The comparative assessment of the novel correlation method with existing prediction methods of human V(ss) was done using a literature dataset of 61 basic drugs (at least one pK(a) > or = 7). The five existing V(ss) prediction methods published in the literature are comprised of four versions of tissue composition-based models along with the model of Lombardo using the principle of Oie-Tozer. The statistical analysis of the prediction performance indicated that the novel method demonstrated a greater degree of accuracy compared to all other published methods. The maximum percentage of predicted values that fall within a twofold-error range is 77% for the basic drugs tested. Overall, the present study describes the development and the assessment of the predictive performance of the novel prediction method of human V(ss) based upon in vitro data, which appears to be superior based on the current dataset studied for basic drugs.

Publication types

  • Comparative Study

MeSH terms

  • Adipose Tissue / metabolism
  • Algorithms
  • Animals
  • Erythrocytes / metabolism
  • Extracellular Space / metabolism
  • Forecasting
  • Humans
  • Models, Statistical
  • Pharmaceutical Preparations / chemistry
  • Pharmaceutical Preparations / metabolism*
  • Pharmacokinetics
  • Phospholipids / metabolism
  • Rats
  • Solubility
  • Species Specificity
  • Tissue Distribution


  • Pharmaceutical Preparations
  • Phospholipids