Consideration of reliable concentrations for prediction of change in enzyme activity by mechanism-based inactivation using physiologically-based pharmacokinetic model simulations

Drug Metab Pharmacokinet. 2010;25(4):335-42. doi: 10.2133/dmpk.dmpk-09-rg-066.

Abstract

Using physiologically-based pharmacokinetic model simulations with the assumption that elimination of inactivator is not altered by mechanism-based inactivation (MBI) of the target enzyme, we examined at what concentrations the influence of MBI could be accurately and simply predicted. The method utilizing maximum unbound systemic concentration as the inactivator concentration (method 1) tended to overestimate this influence, and accuracy expressed as the ratio of estimated and exact fold decrease in enzyme activity ranged from 0.80 to 8.41. In addition, when the volume of distribution was large or the absorption rate constant was small, method 1 provided relatively precise estimation, with the ratio of nearly 1. We propose use of two concentrations, the steady-state average unbound liver concentration and maximum limit of steady-state average unbound liver concentration, to predict the effects of MBI. The accuracy of prediction of MBI using these two concentrations ranged from 0.90 to 1.04 and 0.92 to 2.96, respectively, and was higher than that with method 1. These two concentrations can be obtained early in the drug development process, and estimated results can be expected to contribute to determination of the effects of MBI.

MeSH terms

  • Area Under Curve
  • Computer Simulation
  • Cytochrome P-450 Enzyme Inhibitors*
  • Drug Interactions
  • Humans
  • Liver / metabolism
  • Models, Biological
  • Pharmacokinetics*

Substances

  • Cytochrome P-450 Enzyme Inhibitors