Enhancement of systemic and CNS delivery of meptazinol hydrochloride by intranasal administration to rats.

AIM: To investigate the extent of systemic absorption and uptake of meptazinol (MEP) hydrochloride in cerebrospinal fluid (CSF) after intranasal administration on rats and compare with oral administration. METHODS: CSF samples were collected by a serial sampling method. The concentration of MEP in the biological samples was measured by HPLC with fluorescence detector. RESULTS: Rapid and significant levels of MEP in plasma and CSF can be achieved after nasal administration whereas the oral administration resulted in considerably lower drug concentrations. AUC in plasma and CSF from the nasal route are 7.375 and 15.6 folds compared with those of the oral route, respectively. CONCLUSION: Intranasal MEP is able to show quick absorption and improve the bioavailability, which could be a promising alternative to oral administration.

Pharmacokinetic behavior in plasma, cerebrospinal fluid and cerebral cortex after intranasal administration of hydrochloride meptazinol.

The aim of this paper is to investigate the pharmacokinetic behavior of hydrochloride meptazinol (MEP) in plasma, cerebrospinal fluid (CSF) and cerebral cortex after intranasal administration (8 mg/kg) in male Sprague-Dawley rats. The pharmacokinetic study of intravenous administration (8 mg/kg) was also performed in rats. CSF and cerebral cortex samples were collected by serial CSF sampling and intracerebral microdialysis, respectively. The concentration of MEP in the biological samples was measured by high performance liquid chromatography (HPLC). It was determined that the absorption of MEP from the nasal cavity to systemic circulation was rapid and complete. The concentration-time profile showed a prolonged duration of MEP concentration in CSF and cortex following intranasal administration. The ratios of AUC values of intranasal to intravenous administrations were 0.96, 1.07 and 1.81 in plasma, CSF and cortex dialysate, respectively. In conclusion, intranasal administration of MEP is a promising alternative to traditional administration modes. Olfactory mucosa did not present intranasal MEP another pathway, in addition to systemic absorption, for transport to the brain.

A novel method to calculate the extent and amount of drug transported into CSF after intranasal administration.

The aim of this paper is to establish a novel method to calculate the extent and amount of drug transported to brain after administration. The cerebrospinal fluid (CSF) was chosen as the target region. The intranasal administration of meptazinol hydrochloride (MEP) was chosen as the model administration and intravenous administration was selected as reference. According to formula transform, the extent was measured by the equation of X(A)CSF, infinity/X0 = Cl(CSF) AUC(0-->infinity)CSF/X0 and the drug amount was calculated by multiplying the dose with the extent. The drug clearance in CSF (Cl(CSF)) was calculated by a method, in which a certain volume of MEP solution was injected directly into rat cistern magna and then clearance was assessed as the reciprocal of the zeroth moment of a CSF level-time curve normalized for dose. In order to testify the accurateness of the method, 14C-sucrose was chosen as reference because of its impermeable characteristic across blood-brain barrier (BBB). It was found out that the MEP concentrations in plasma and CSF after intranasal administration did not show significant difference with those after intravenous administration. However, the extent and amount of MEP transported to CSF was significantly lower compared with those to plasma after these two administrations. In conclusion, the method can be applied to measure the extent and amount of drug transported to CSF, which would be useful to evaluate brain-targeting drug delivery.

Disposition and pharmacokinetics of meptazinol in the CSF. Studies after intrathecal administration in the non-human primate Erythrocebus patas.

A preliminary study is reported on the kinetics of meptazinol following intrathecal and i.m. administration in the Patas monkey. Following intrathecal administration (single dose of 0.5 mg) at T12/L1, meptazinol rapidly disappeared from the CSF with a T1/2 of 35 min. At 240 min after intrathecal injection, most of the meptazinol had been distributed within the spinal tissue near the region of the injection, with minimal amounts reaching the brain (less than 5% of the concentrations present in the lumbar and thoracic tissue). Following i.m. administration (16 mg kg-1) peak concentrations were present in the CSF and plasma within 60 min. Appreciable concentrations persisted in the CSF up to 180 min after i.m. administration. The results would suggest that meptazinol should give rapid but short acting pain relief following intrathecal injection with minimal CNS-related side effects.