Inter- and intra-subject variation in the first-pass elimination of highly cleared drugs during chronic dosing. Studies with deuterated verapamil.
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.
D000284:Administration, Oral; D000328:Adult; D001682:Biological Availability; D003903:Deuterium; D005260:Female; D006207:Half-Life; D006801:Humans; D007700:Kinetics; D008297:Male; D013997:Time Factors; D014700:Verapamil / Q000097:blood*
D003903:Deuterium; D014700:Verapamil