Disposition and pharmacologic effects of R/S-verapamil in patients with chronic atrial fibrillation: An investigation comparing single and multiple dosing

Background: Racemic (R/S)-verapamil is widely used in the management of chr onic atrial fibrillation. The negative dromotropic effect is mainly mediate d by the S-enantiomer, which is preferentially metabolized. Previous studie s report an accumulation of R/S-verapamil during long-term oral treatment o f patients with chronic atrial fibrillation. However, the specific disposit ion of S-verapamil and the pharmacologic effects were not assessed, Therefo re uncertainties about the need for dose adjustments remain. Methods: Using stable isotope technology and a stereospecific assay, we com pared the pharmacokinetics and pharmacodynamics of intravenous (10 mg of d( 7)-R/S-verapamil) and oral (240 mg of slow release (SR) d(0)-R/S-verapamil) R-verapamil and S-verapamil after the first dose (day 1) and after 3 weeks (day 21) of continuous oral therapy in 8 patients with long-term atrial fi brillation. On both study days, serum samples were obtained for the analysi s of d(7)- and d(0)-R-verapamil and S-verapamil, Heart rate (HR) was monito red with electrocardiography (with each blood sample) and Holter electrocar diography (before the study, on day 1, and on day 21). Results: Compared with day 1, clearance of oral R-verapamil and S-verapamil was significantly reduced on day 21 (1007 +/- 380 versus 651 +/- 253 mL/mi n [-35%] and 5481 +/- 2731 versus 2855 +/- 1097 mL/min [-48%], respectively ; P < .05), whereas only a moderate decrease was observed for intravenous R -verapamil and S-verapamil (-23% and -14%, respectively, not significant). Mean HR (89 <plus/minus> 11 bpm before verapamil) was effectively reduced, with the same effects on day 1 (68 +/- 8 bpm) and day 21 (68 +/- 8 bpm). Co mpared with day 1, the HR reduction per ng/mL of S-verapamil (calculated by the area under the curve [from 0-24 hours] ratio of HR reduction and S-ver apamil concentration) was significantly lower on day 21 (0.7 +/- 0.4 versus 1.2 +/- 0.7 [bpm] [ng/mL](-1), for day 21 versus day 1; P < .01). Conclusions: In patients with chronic atrial fibrillation, clearance of ora l, but not intravenous, S-verapamil and R-verapamil is significantly reduce d with multiple doses compared with a single dose, thereby indicating predo minant: impairment of prehepatic rather than hepatic metabolism as the unde rlying mechanism. However, this kinetic change is clinically compensated by a decrease in the responsiveness to S-verapamil observed with regular dosi ng. The data suggest that despite accumulation of the drug individual verap amil doses can be maintained during long-term oral rate control therapy.