Central nervous system exposure of next generation quinoline methanols is reduced relative to mefloquine after intravenous dosing in mice.

ABSTRACT:

Background

The clinical use of mefloquine (MQ) has declined due to dose-related neurological events. Next generation quinoline methanols (NGQMs) that do not accumulate in the central nervous system (CNS) to the same extent may have utility. In this study, CNS levels of NGQMs relative to MQ were measured and an early lead chemotype was identified for further optimization.

Experimental design

The plasma and brain levels of MQ and twenty five, 4-position modified NGQMs were determined using LCMS/MS at 5 min, 1, 6 and 24 h after IV administration (5 mg/kg) to male FVB mice. Fraction unbound in brain tissue homogenate was assessed in vitro using equilibrium dialysis and this was then used to calculate brain-unbound concentration from the measured brain total concentration. A five

SUBMITTER: Dow GS 

PROVIDER: S-EPMC3128011 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature