Abstract
In the present study, several nasal absorption enhancers, used in metoclopramide hydrochloride (MCP HCl) nasal solutions, have been screened for their possible damaging effect in the
in vitro human erythrocytes lysis experiment. Moreover, the
in vivo leaching of biological markers from the rat nasal epithelium was used as a quantitative assessment for possible nasal mucosal irritation whereby the extent of release of total protein and lactate dehydrogenase (LDH) in the nasal lavage fluid was determined. Results showed that insignificant hemolysis from normal saline (
P
<
0.05) occurred with the enhancer protamine sulphate while poly-
l-arginine and sodium cholate demonstrated very low (<15%) hemolysis and caused insignificant protein and LDH release from the rat nasal mucosa. Conversely, sodium deoxycholate and chitosan polymers (either of low or high molecular weight) showed high (>60%) hemolysis
in vitro and the release of the biological markers
in vivo was significantly higher (
P
<
0.05) than the control solution (no enhancer).
A significant correlation (
P
<
0.05) existed between the enhancement effect of MCP HCl nasal absorption and the amounts of protein (
r
=
0.85) and LDH (
r
=
0.88). Furthermore, the pharmacokinetics of MCP HCl was determined after intravenous (IV), per-oral and intranasal administration of 10
mg drug dose in rabbits. The application of a nasal spray (NS) solution containing 0.5% sodium cholate resulted in a significant improvement (
P
<
0.05) in both the rate and extent of absorption of MCP HCl where the
T
max achieved was 23.3
min as compared to 50
min in case of the oral solution while the area under the serum concentration–time curve (AUC
0–∞) were 506.1, 434.9 and 278.7
μg/ml
min for IV, NS and oral solutions, respectively. These values corresponded to absolute bioavailabilities of 87.21 and 55.61% for the NS and oral solutions, respectively. It could thus be concluded that NS of MCP HCl represents a viable approach to achieving rapid and high systemic drug absorption during the emergency treatment of severe emesis.