Prediction of inter-individual variability on the pharmacokinetics of CYP1A2 substrates in non-smoking healthy volunteers

Drug Metab Pharmacokinet. 2016 Aug;31(4):276-84. doi: 10.1016/j.dmpk.2016.03.003. Epub 2016 Mar 24.


The activity of CYP1A2, a major drug-metabolizing enzyme, is known to be affected by various environmental factors. Our study aimed to predict inter-individual variability of AUC/Dose of CYP1A2 substrates in non-smoking healthy volunteers using the Monte Carlo simulation. Inter-individual variability in hepatic intrinsic clearance of CYP1A2 substrates (CLint,h,1A2) was estimated using dispersion model based on the inter-individual variability (N = 96) of the AUC of caffeine, a major CYP1A2 substrate. The estimated coefficient of variation (CV) of CLint,h,1A2 was 55%, similar to previously reported CLint,h,2D6 (60%) but larger than CLint,h,3A4 (33%). Then, this estimated CV was validated by predicting the CVs of AUC/Dose of tizanidine and phenacetin, which are mainly metabolized by CYP1A2 and have negligible renal clearance. As a result, reported CVs were successfully predicted within 2.5-97.5 percentile range of predicted values. Moreover, CVs for AUC/Dose of the CYP1A2 substrates theophylline and lidocaine, which are affected by other CYPs and renal clearance, were also successfully predicted. The inter-individual variability of AUC/Dose of CYP1A2 substrates was successfully predicted using 55% CV for CLint,h,1A2, and the results, along with those reported by our group for other CYPs, support the prediction of inter-individual variability of pharmacokinetics in the clinical setting.

Keywords: CYP1A2; Drug development; Human pharmacokinetics; Inter-individual variability; Monte Carlo simulation.

MeSH terms

  • Area Under Curve
  • Caffeine / pharmacokinetics
  • Clonidine / analogs & derivatives
  • Clonidine / pharmacokinetics
  • Cytochrome P-450 CYP1A2 / metabolism*
  • Healthy Volunteers
  • Humans
  • Lidocaine / pharmacokinetics
  • Monte Carlo Method
  • Phenacetin / pharmacokinetics
  • Theophylline / pharmacokinetics


  • Caffeine
  • tizanidine
  • Lidocaine
  • Theophylline
  • CYP1A2 protein, human
  • Cytochrome P-450 CYP1A2
  • Phenacetin
  • Clonidine