Simultaneous first-order and capacity-limited elimination kinetics after oral administration of verapamil.
In this study of the relationship between dose and plasma concentration of verapamil, controlled-release verapamil in doses of 120 mg, 180 mg, 360 mg, and 540 mg were examined. The 48 study subjects received verapamil daily during each of the 4 sequential 5-day dosing segments. Blood samples were collected frequently to obtain first-dose and steady-state (fifth dose) concentration profiles of verapamil. Plasma concentrations of R- and S-verapamil and R- and S-norverapamil were measured by stereospecific assay. Statistical comparisons of pharmacokinetic parameters and mean differences between doses were performed with analysis of variance models. At steady state, area under the concentration-time curve (AUC) values for R- and S-verapamil at both the 120-mg and 180-mg doses were about 1.5 times higher than the corresponding first-dose values. After both first and fifth doses, pharmacokinetic parameters for all four analytes were dose proportional between the 120-mg and 180-mg doses. A dose-proportional relationship also was found between the 360-mg and 540-mg dose levels. However, nonlinearity was found between the 180-mg dose and higher doses, suggesting saturable metabolic pathways. The dose-proportional relationship between the 360-mg and 540-mg doses suggests that other first-order metabolic pathways become dominant. Although results from this study are partially consistent with previously reported nonlinear verapamil kinetics, this is the first clinical study to demonstrate a dose-proportional relationship for verapamil at both low and high input rates (mg/hr). In addition, first-order disposition pathways of verapamil are probably nonexistent at medium input rates and become dominant at higher input rates.
Gupta
S K
SK
ALZA Corporation, Palo Alto, California, USA.
Hwang
S
S
Atkinson
L
L
Longstreth
J
J
D000284:Administration, Oral; D000328:Adult; D002121:Calcium Channel Blockers / Q000097:blood / Q000493:pharmacokinetics*; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D006801:Humans; D008297:Male; D008875:Middle Aged; D014700:Verapamil / Q000097:blood / Q000493:pharmacokinetics*
D002121:Calcium Channel Blockers; D003692:Delayed-Action Preparations; D014700:Verapamil