Chronopharmacology of intravenous and oral modified release verapamil

Aims Using a stable isotope technique which allows simultaneous and differential measuring of orally and intravenously administered drugs we compared the pharmacokinetics and pharmacodynamics of unlabelled modified release verapamil po (steady state) and deuterated verapamil i.v. (single dose) following morning and evening administration. Methods Twelve female and 12 male healthy volunteers were studied in a randomized, crossover design. During the last day of each treatment period (day 6 and day 10) pharmacokinetics and pharmacodynamics (PR interval) of verapamil were assessed; 1 h before ingestion of a new R/S-verapamil 240 mg modified release formulation (08.00 h vr 20.00 h) a single dose of 10 mg d(7)-R/S-verapamil was administered intravenously. Serum levels of unlabelled and labelled R/S-verapamil were measured by gas chromatography/mass spectrometry. In selected samples of serum which were chosen at t(min,po) and t(max,po) the enantiomers were separated by chiral high-performance liquid chromatography in order to calculate R- to S-verapamil serum concentration ratios. Results We observed no significant differences in pharmacokinetics (AUC(po), C-max, t(max), CLo, F and R/S enantiomer ratio) between morning and evening treatment with modified release verapamil and there was no influence of time of dosing on mean prolongation of PR interval. AUG(iv), CL, V-ss and d(7)-R/d(7)-S enantiomer ratio following verapamil i.v. did not show circadian variation. t(1/2) was slightly but statistically significantly increased after the morning infusion. PR-prolongation was significantly greater after verapamil i.v. in the morning than in the evening. The 90% confidence intervals of the differences between morning and evening administration in AUC(po), C-max and AUC(iv) were within the equivalence range of 0.8-1.25. Conclusions Time of dosing has no significant influence on pharmacokinetics and pharmacodynamics of this new modified release formulation of verapamil. Circadian variation in presystemic metabolism of verapamil was not observed.