Comparative pharmacokinetics of single doses of doxylamine succinate following intranasal, oral and intravenous administration in rats

The intranasal route of administration provides a potential useful way of administering a range of systemic drugs. In order to assess the feasibility of this approach for the treatment of nausea and vomiting, doxylamine succinate was studied in rats for the pharmacokinetics (AUC, Cmax, tmax) following intranasal, oral and intravenous administrations. Subjects (six male Sprague–Dawley rats per time interval for each route of administration) received 2‐mg doses of doxylamine succinate orally and I‐mg doses intranasally and intravenously, respectively. The various formulations were formulated in isotonic saline (0.9% w/v) at 25±1°C. Doxylamine succinate concentrations in plasma were determined with a high‐performance liquid chromatographic assay and a liquid–liquid extraction procedure. Intranasal and oral bioavailabilities were determined from AUC values relative to those after intravenous dosing. Intranasal bioavailability was greater than that of oral doxylamine succinate (70.8 vs 24.7%). The intranasal and oral routes of administration differed significantly from the intravenous route of administration. Peak plasma concentration (Cmax) was 887.6 ng/ml (S.D. 74.4), 281.4 ng/ml (S.D. 24.6) and 1296.4 ng/ml (S.D. 388.9) for the intranasal, oral and intravenous routes, respectively. The time to achieve Cmax for the intranasal route (tmax=0.5 h) was faster than for the oral route (tmax=1.5 h), but no statistically significant differences between the Cmax values were found using 95% confidence intervals. The results of this study show that doxylamine succinate is rapidly and effectively absorbed from the nasal mucosa. Copyright © 2002 John Wiley & Sons, Ltd.