VERAPAMIL NASAL DRUG DELIVERY AND STEREOSELECTIVE DISPOSITION IN RATS

The bioavailability of verapamil after oral administration is poor and highly variable. These factors combined with its stereoselective first-pass metabolism in humans after oral administration may contribute to its diminished oral therapeutic efficacy. Consequently, an alternative non-parenteral route for administration of this drug appears warranted. The potential utility of a nasal verapamil dosage form to achieve this goal was investigated by characterizing the effect of this route of administration on verapamil disposition and availability in the rat.;The brain levels of verapamil over time were lower in rats during the first twenty minutes after nasal verapamil administration compared with rats administered verapamil by the intravenous route. Based on these results, no special therapeutic advantage or improved delivery of drugs to the central nervous system would be anticipated following nasal drug dosing.;The administration of verapamil by nasal route enhanced its bioavailability (F(,n) = 1.0) compared to that following oral administration (F(,o) = 0.07) (p < 0.05). In addition to the poor oral availability of verapamil, stereoselective first-pass removal of the most active verapamil enantiomer was also observed. The l-enantiomer of verapamil exhibited a higher oral clearance (Cl(,o)('l) = 440 ml/min.) and lower systemic availability (F(,o)('l) = 0.05) than the d-isomer (Cl(,o)('d) = 175 ml/min.; F(,o)('d) = 0.12) (p < 0.05). No significant difference in the clearance or availability of these enantiomers, however, was detected following their nasal administration (Cl(,n)('d&l) = 19 ml/min.; F(,n)('d&l) = 1.0). These results indicate nasal administration of verapamil may improve its systemic availability and avoid the current delivery problems presently associated with oral verapamil dosing. (Abstract shortened with permission of author.).;For this work, a high performance liquid chromatographic assay was developed for quantitation of verapamil and its N-demethylated metabolite, norverapamil, in small blood samples from the rat. Dose dependent first-pass metabolism of verapamil and its possible contribution to norverapamil formation after oral verapamil administration was also investigated. Finally, the delivery of verapamil to the brain was compared following its nasal and intravenous administration to determine whether any additional therapeutic advantages may be associated with nasal drug dosing.