An investigation of the cause of accumulation of verapamil during regular dosing in patients.

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)