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

Abstract

BackgroundThe 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 designThe 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-fold reduction CNS levels relative to mefloquine was considered acceptable. Additional pharmacological properties such as permeability and potency were determined.ResultsThe maximum brain (whole/free) concentrations of MQ were 1807/4.9 ng/g. Maximum whole brain concentrations of NGQMs were 23 - 21546 ng/g. Maximum free brain concentrations were 0.5 to 267 ng/g. Seven (28%) and two (8%) compounds exhibited acceptable whole and free brain concentrations, respectively. Optimization of maximum free brain levels, IC90s (as a measure or potency) and residual plasma concentrations at 24 h (as a surrogate for half-life) in the same molecule may be feasible since they were not correlated. Diamine quinoline methanols were the most promising lead compounds.ConclusionReduction of CNS levels of NGQMs relative to mefloquine may be feasible. Optimization of this property together with potency and long half-life may be feasible amongst diamine quinoline methanols.

Characterization of the Preclinical Pharmacology of the New 2-Aminomethylphenol, JPC-3210, for Malaria Treatment and Prevention

“…In the present study, JPC-3210 was found to concentrate in the brain, with a mean Ϯ SD brain tissue-to-plasma ratio (Kp) of 4.6 Ϯ 1.4 at 2 h, 5.0 Ϯ 0.7 at 24 h, and 6.7 Ϯ 1.3 at 72 h after oral administration of JPC-3210 in mice, which are in accord with its relatively high apparent volume of distribution and lipophilic properties. In comparison to JPC-3210, mefloquine, a drug that can cause neurological disturbances in some individuals due to its highly lipophilic properties and extensive distribution to tissues, has a Kp of 3.9 at 24 h after intravenous administration of the drug in mice (18). However, Kp is based on a crude homogenization of brain tissue and as such ignores the compartmentalization of the brain.…”

Potentiation of Amitriptyline Anti-Hyperalgesic-Like Action By Astroglial Connexin 43 Inhibition in Neuropathic Rats

“…This observation, suggesting the occurrence of some synergy between the in vitro effects of mefloquine and amitriptyline, led us to investigate whether a similar interaction might also occur in vivo . Indeed, mefloquine appeared especially relevant for such studies because it crosses the blood brain barrier46. Furthermore, its pharmacological profile indicates a relatively good selectivity as a Cx channel inhibitor.…”

Mefloquine and psychotomimetics share neurotransmitter receptor and transporter interactions in vitro

“…Comparing free to whole mouse brain concentrations following a single i.v. dose, Dow et al, 2011) calculated a ratio of 4.9/1807, or 0.0027, with a whole brain concentration of about 4μM, and about 18 nM free brain mefloquine in mice. However, soldiers taking the drug prophylactically and who were killed in the line of duty had brain levels of 8.7 to 14 mg/kg (Jones et al, 1994).…”