| Summary: | 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 a nd 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. === Thesis (M.Sc. (Pharm.))--North-West University, Potchefstroom Campus, 2004.
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