Hongna Wang1, Anwar A Hussain, Peter J Wedlund. 1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky 40536, USA.
Abstract
PURPOSE: The purpose of this research was to characterize nipecotic acid pharmacokinetics in blood and brain after intravenous (i.v.) and nasal administration of nipecotic acid and its n-butyl ester. METHODS: Nipecotic acid and its n-butyl ester were administered to rats i.v. and intranasally (n = 5 rats/drug per route), and nipecotic acid pharmacokinetics in blood were characterized. Nipecotic acid concentration-time profiles were determined in blood by noncompartmental and compartmental methods. Nipecotic acid was also dosed i.v. and its n-butyl ester was dosed by nasal and i.v. routes, and brain levels of nipecotic acid over the subsequent 4 h (n = 5 rats/time point per route) were assessed. RESULTS: The absolute systemic availability of nipecotic acid after nasal dosing was 14%. After i.v. and nasal dosing of the n-butyl ester, nipecotic acid systemic availability was 97% and 92%, respectively. Both i.v. and nasal administration of the n-butyl ester resulted in a significantly longer terminal half-life and larger mean resident time and volume of distribution for nipecotic acid than was observed after an i.v. nipecotic acid dose. Total brain exposure to nipecotic acid was not significantly different after nasal and i.v. dosing of the n-butyl ester. However, the brain/blood nipecotic acid ratio declined significantly with time after i.v. and nasal dosing of the ester prodrug. Nipecotic acid was not detectable in brain after i.v. dosing of nipecotic acid. CONCLUSIONS: The use of an ester formulation was crucial to delivering nipecotic acid to the brain. Preliminary evidence strongly suggests ester hydrolysis is rate limiting to nipecotic acid brain delivery. Once nipeoctic acid was formed, it displayed tissue trapping in brain. Parenteral dosing of nipecotic acid esters is unnecessary for systemic or brain delivery of nipecotic acid and possibly other CNS active zwitterion esters.
PURPOSE: The purpose of this research was to characterize nipecotic acid pharmacokinetics in blood and brain after intravenous (i.v.) and nasal administration of nipecotic acid and its n-butyl ester. METHODS:Nipecotic acid and its n-butyl ester were administered to rats i.v. and intranasally (n = 5 rats/drug per route), and nipecotic acid pharmacokinetics in blood were characterized. Nipecotic acid concentration-time profiles were determined in blood by noncompartmental and compartmental methods. Nipecotic acid was also dosed i.v. and its n-butyl ester was dosed by nasal and i.v. routes, and brain levels of nipecotic acid over the subsequent 4 h (n = 5 rats/time point per route) were assessed. RESULTS: The absolute systemic availability of nipecotic acid after nasal dosing was 14%. After i.v. and nasal dosing of the n-butyl ester, nipecotic acid systemic availability was 97% and 92%, respectively. Both i.v. and nasal administration of the n-butyl ester resulted in a significantly longer terminal half-life and larger mean resident time and volume of distribution for nipecotic acid than was observed after an i.v. nipecotic acid dose. Total brain exposure to nipecotic acid was not significantly different after nasal and i.v. dosing of the n-butyl ester. However, the brain/blood nipecotic acid ratio declined significantly with time after i.v. and nasal dosing of the ester prodrug. Nipecotic acid was not detectable in brain after i.v. dosing of nipecotic acid. CONCLUSIONS: The use of an ester formulation was crucial to delivering nipecotic acid to the brain. Preliminary evidence strongly suggests ester hydrolysis is rate limiting to nipecotic acid brain delivery. Once nipeoctic acid was formed, it displayed tissue trapping in brain. Parenteral dosing of nipecotic acid esters is unnecessary for systemic or brain delivery of nipecotic acid and possibly other CNS active zwitterion esters.
Authors: K E Andersen; J L Sørensen; J Lau; B F Lundt; H Petersen; P O Huusfeldt; P D Suzdak; M D Swedberg Journal: J Med Chem Date: 2001-06-21 Impact factor: 7.446
Authors: K E Andersen; J Lau; B F Lundt; H Petersen; P O Huusfeldt; P D Suzdak; M D Swedberg Journal: Bioorg Med Chem Date: 2001-11 Impact factor: 3.641
Authors: L J Knutsen; K E Andersen; J Lau; B F Lundt; R F Henry; H E Morton; L Naerum; H Petersen; H Stephensen; P D Suzdak; M D Swedberg; C Thomsen; P O Sørensen Journal: J Med Chem Date: 1999-09-09 Impact factor: 7.446