Inter- and intra-subject variation in the first-pass elimination of highly cleared drugs during chronic dosing. Studies with deuterated verapamil

Eur J Clin Pharmacol. 1984;26(1):47-53. doi: 10.1007/BF00546708.


The pharmacokinetics of verapamil in five healthy volunteers were investigated on 4 occasions during chronic administration of deuterated verapamil. There was no statistically significant difference in oral clearance, terminal half-life, bioavailability, morning trough level and peak concentration or in the time of their occurrence on the four occasions. The plasma clearance, however, exhibited considerable inter- and intra-individual variation, ranging between 26.3% and 85.4% and 12.0% and 48.0%, respectively. Comparison of these pharmacokinetic parameters with data from previous single dose studies in the same subjects revealed a significant (p less than 0.05) decrease in the clearance and an increase in the apparent bioavailability of verapamil during chronic administration, although no difference in the half-life was found. Due to the considerable variation in the oral clearance of verapamil during chronic dosing, steady-state conditions in a strict pharmacokinetic sense may never be attained, and pharmacokinetic data obtained in single dose studies will be of limited value in predicting steady-state plasma concentrations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Biological Availability
  • Deuterium
  • Female
  • Half-Life
  • Humans
  • Kinetics
  • Male
  • Time Factors
  • Verapamil / blood*


  • Deuterium
  • Verapamil