Chronopharmacology of Verapamil in Hypertension: Pp.25.02

Objective: The aim of the trial was to study the pharmacokinetics of morning and evening intake of verapamil retard and to compare these data with 24-hour antihypertensive effect of the drug. Design and Method: 14 volunteers (5 males, mean age 62 ± 2 years) with stable hypertension (mean day-time blood pressure (BP) >135/85 mm Hg) were enrolled into the open, randomized, cross-over trial. Before the trial started, all antihypertensive medications were withdrawn, with an exception of short-acting agents. The duration of the initial wash-out period was 2 weeks; the duration of both “morning” and “evening” treatment courses – 3 weeks; the interval between courses - 1 week. The dose of verapamil (isoptin-SR) was 240 mg o.d. The plasma concentration of non-modified verapamil was measured by high-performance liquid chromatography with fluorescent detection. BP monitoring (Spacelabs 90207) was performed prior to treatment and at the end of each course of treatment, simultaneously with the verapamil concentration measurement. The Spearman partial coefficient with z-transformation was used in correlation analysis. Results: The maximal plasma concentration of verapamil after its morning intake was 239.7 ± 152.3 ng/ml (M ± SD), after the evening intake – 148.6 ± 107.4 ng/ml (p < 0,01). The half-elimination time was 12.5 ± 3.5 h and 22.6 ± 15.2 h (p < .05), respectively. We found no significant differences in other pharmacokinetic parameters. The correlation coefficients between 24 hour systolic BP changes and drug concentrations were -0.134 ± 0.050 for morning intake and -0.242 ± 0.081 for evening intake (p < 0,05). Conclusions: Morning intake of verapamil in hypertensive patients resulted in rapid increase of drug plasma concentration. At the same time, evening administration of verapamil was associated with higher half-elimination time and “concentration-effect” correlation. According to our data, the evening verapamil intake should be more effective and cause less adverse events. We propose that our analytical model may be used for the identification of the most rational time regimen of different antihypertensive drugs administration.