Simultaneous First‐Order and Capacity‐Limited Elimination Kinetics After Oral Administration of Verapamil

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Abstract
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.

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