Comparative bioavailability of prochlorperazine edisylate in plasma and brain tissue after intravenous, oral and intranasal administration
The nasal administration of drugs offers advantages over administration by intravenous injection. Drugs can be rapidly absorbed through the nasal mucosa, resulting in a rapid onset of action, and also avoiding degradation in the gastro-intestinal tract and first-pass metabolism in the liver. Targeting the brain via nasal administration offers potential for the development of new drug products. The olfactory cells are in direct contact with both the environment and the central nervous system (CNS). The olfactory pathway thus circumvents the blood-brain barrier (BBB), which prevents many systemically administered drugs from entering the brain. A literature study concerning the anatomy and physiology oft he nose, factors affecting the absorption of nasally administered drugs; different mechanisms to enhance nasal drug absorption as well as the general characteristics of prochlorperazine edisylate were performed. As a result of the literature study, it was concluded that the nasal route is suited for administration and absorption of prochlorperazine edisylate. The aim of this study was to compare the concentrations of prochlorperazine found in plasma and brain tissue of rats, after intravenous, oral and intranasal administration. Methods: In order to investigate the objective, a dose of 0.167 mg/kg prochlorperazine edisylate was administered intravenously (100 µI), nasally (50 µl) and 1.333 mg/kg was administered orally (100 µl). The concentrations were corrected for the different dosages in order to compare the respective bioavailabilities. The nasal bioavailability of prochlorperazine was investigated in a rat model: uptake in the brain tissue and plasma levels were compared after intravenous, oral and intranasal administration. A liquid-liquid extraction method for the quantitative determination of prochlorperazine in brain tissue and a solid-phase extraction method for the quantitative determination of prochlorperazine in plasma were used. The concentrations of prochlorperazine in plasma and brain tissue were measured with high performance liquid chromatography. Results: The results indicate that the nasal administration of prochlorperazine is an easy and workable alternative to intravenous injections, which may enhance patient compliance. Nasal absorption: The concentration-time profile achieved after nasal administration of prochlorperazine is similar to that achieved after intravenous administration. The absorption of prochlorperazine edisylate from the nasal cavity into the systemic circulation was rapid and almost complete. The AUC-values, used as an indication of the extent of absorption, for the intravenous (3371.47 ± 173.79 ng/ml/h), intranasal (2936.71 ± 189.65 ng/ml/h) and oral routes of administration (718.07 ± 42.74 ng/ml/h) were compared. Compared to the intravenous route of administration (100%), the nasal route showed an absolute bioavailability of 87.10% and the oral route 21.30%. A low oral bioavailability was achieved, as expected, due to degradation in the gastro-intestinal tract and firstpass metabolism in the liver. Uptake into the brain tissue: The concentration-time profiles of prochlorperazine in brain tissue showed no increased maximum concentrations of drug after nasal administration compared to intravenous administration. However, this concentration was retained longer after nasal administration compared to intravenous administration. No direct evidence for transfer along the olfactory pathway was shown with prochlorperazine. The intranasal/intravenous brain tissue concentration ratio exceeded one after 30 and 45 minutes after nasal administration at a pH of 6.6 and 4.65 respectively, indicating that after these time intervals the concentrations of nasally administered prochlorperazine in the brain tissue were higher than those after intravenous administration. Prochlorperazine concentrations in the brain tissue were significantly higher after nasal administration than after oral administration. Significant concentrations of prochlorperazine were found in the brain tissue as early as 5 minutes after nasal administration. The AUC-values after nasal (96745.32 ± 3649.65 ng/g/h), intravenous (90051.71 ± 6189.75 ng/g/h) and oral administration (12507.20 ± 1248.01 ng/g/h) indicated that the nasal/intravenous AUC ratio in brain tissue was found to be greater than one. Conclusion: Nasal administration of CNS-active anti-emetic drugs with low oral bioavailability could be used as an alternative for the intravenous route of administration. The lipophilic drug, prochlorperazine was rapidly and almost completely absorbed after nasal administration. These molecules appeared rapidly in the brain tissue. Although hard evidence of direct transfer from the nose remains elusive, the fact that a higher AUC-value was obtained after nasal than after intravenous administration was evidence enough that the olfactory route does contribute to the delivery of drugs to the brain after nasal administration.
- Health Sciences