DISTRIBUTION OF ANTIHISTAMINES INTO THE CSF FOLLOWING INTRANASAL DELIVERY

The preferential absorption of certain drug compounds from the nasal c avity into the cerebrospinal fluid (CSF) raises questions regarding th e transport processes controlling drug disposition following intranasa l delivery. The disposition characteristics of several structurally si milar antihistamine compounds, hydroxyzine, chlorpheniramine, triproli dine, and chlorcyclizine, into the CSF following nasal administration were studied using the rat as an animal model. The antihistamines were administered either intranasally or intra-arterially, and serial CSF and plasma samples were collected from the cisterna magna and the femo ral artery, respectively. The drug levels in CSF and plasma were assay ed by HPLC. Hydroxyzine concentrations in plasma and CSF were found to be significantly greater than most of the other compounds tested. In addition, hydroxyzine also showed the most rapid systemic absorption f ollowing nasal administration. Interestingly, the hydroxyzine levels i n CSF following intranasal administration were significantly higher th an those following intra-arterial administration. The AUC ratios betwe en CSF and plasma for hydroxyzine after intranasal and intra-arterial administration were 4.0 and 0.4, respectively. The AUC ratios for trip rolidine, the other antihistamine with measurable CSF concentrations, were 0.5 and 0.7, respectively. The distribution of antihistamines fro m the nasal membrane into the CSF appears to be controlled by a combin ation of their molecular properties. It also appears that the intranas al delivery of drugs with optimal physicochemical characteristics can result in an improved CNS bioavailability compared to those achieved f rom an equivalent parenteral dose. (C) 1997 by John Wiley & Sons, Ltd.