| Abstract: | The accumulation of verapamil during regular dosing conditions was studied. Plasma concentrations of verapamil (V) and norverapamil (NV) were measured as were urinary concentrations of verapamil, norverapamil, and four other N- and O-dealkylated metabolites in nine patients after an initial single dose and after chronic oral verapamil administration to steady-state plasma concentrations. Indocyanine green (ICG) clearance was determined immediately prior to the initial verapamil dose and prior to the verapamil washout from regular dosing. An approximately two-fold accumulation of V had occurred during regular dosing. The area under the plasma concentration-time curve (AUC1) after the first dose was 417.4 +/- 276.7 ng ml-1 h (mean +/- s.d.) and increased to 786.5 +/- 54 ng ml-1 h (P less than 0.01) during one dosage interval at steady-state (AUCss). NV also tended to accumulate from an AUC1 of 552.6 +/- 411 to an AUCss 668.7 +/- 332 ng ml-1 h (P less than 0.09). The ratio of AUC-V to AUC-NV was unchanged. The verapamil elimination half-life (t 1/2) increased from 8.4 +/- 4.2 to 12.0 +/- 3.6 h (P less than 0.01) whereas the norverapamil t 1/2 was unchanged. ICG clearance was unchanged. Urinary excretion of NV increased slightly but the ratio of urinary V/NV concentrations was not significantly altered nor was the ratio of four other metabolites to verapamil or the ratio of the combined o-demethylated to the N-dealkylated metabolites.(ABSTRACT TRUNCATED AT 250 WORDS) |
