Pharmacodynamic profile of verapamil in relation to absolute bioavailability: investigations with a conventional and a controlled-release formulation.
The absolute bioavailability F and response (prolongation of the PR interval) of verapamil after single doses of the same oral formulation administered on two different days were investigated in 16 male subjects with an 80 mg fast dissolving and a 240 mg controlled-release preparation and compared with a bolus injection of 5 mg of verapamil. The absolute bioavailability was 23% in both investigations for the 80 mg preparation and 32% in both investigations for the 240 mg dosage form. The individual values obtained for tmax, cmax, F, and AUC0-alpha showed a wide intersubject variability; therefore, no significant differences could be observed between the two trials for each dosage, but significant differences existed between the investigations of the two preparations. After intravenous administration, concentration-effect curves were about twofold left shifted when compared with the 80 mg tablet and about threefold left shifted when compared with the 240 mg tablet. Estimation of the drug input rate showed significantly (p less than 0.05) smaller values when the controlled-release tablet was given (80 mg tablet: 95.1 and 107.7 mg/h; 240 mg tablet; 55.8 and 46.3 mg/h). Thus, the effect and bioavailability of verapamil show sufficient intersubject reproducibility if the same formulation is given. The differences between the responses and the bioavailability after administration of different preparations may be related as well to the drug absorption rate and the stereoselective first pass of verapamil as to saturation of first-pass metabolism.
Harder
S
S
Department of Clinical Pharmacology, University Hospital Frankfurt/Main, F.R.G.
Thürmann
P
P
Siewert
M
M
Blume
H
H
Huber
T
T
Rietbrock
N
N
D000284:Administration, Oral; D000328:Adult; D001682:Biological Availability; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007262:Infusions, Intravenous; D007408:Intestinal Absorption; D008297:Male; D014700:Verapamil / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology
D003692:Delayed-Action Preparations; C016904:norverapamil; D014700:Verapamil