Comparison of the Pharmacokinetics and Electrocardiographic Effects of Sublingual and Intravenous Verapamil

Using a dog model, a sublingual form of the free base of verapamil (SLV) was developed with the intent of avoiding stereoselective first-pass metabolism and the necessity of intravenous administration. Intravenous verapamil (IVV) 5 mg and SLV 40 mg or 60 mg were sequentially administered to seven healthy human volunteers. Electrocardiograms and serum concentrations were obtained before and periodically from 5 to 480 minutes after each dose. The time to peak serum concentration (mean ± SD) was 77.6 ± 38.1 minutes after SLV. Bioavailability of SLV was 58.2 ± 36.9% compared to IVV. Verapamil half-lives after IVV and SLV were 2.83 ± 0.93 and 2.28 ± 0.45 hours (NS), respectively. In one subject, the time to peak effect was delayed and overall change in PR interval was minimum. In the remaining six subjects, the maximum percentage increases in PR interval after IVV and SLV were 20.6 ± 6.4% and 14.8 ± 5.5% (p<0.05), respectively. Times to peak increase in PR interval were 28.3 ± 15.7 and 57.0 ± 17.5 minutes after IVV and SLV (p<0.05), respectively. Analysis of plots of percentage change in PR interval versus serum concentration revealed a shift to the right and therefore, lesser effect of SLV than of IVV in six subjects. All seven subjects complained of oral numbness and bitter taste. In conclusion, SLV is inferior to IVV in terms of rate and extent of absorption and pharmacologic effect in delaying atrioventricular nodal conduction. Probably SLV has little clinical utility because of its slow onset and poor tolerance.