A Quantitative Analysis of Memantine in Human Plasma Using Ultra Performance Liquid Chromatography/Tandem Mass Spectrometry

Sunil K Dubey,Rakesh Jain,Arun Kumar,Simrit Reyar,Nageshwar R Thudi,Anil Patni,Arshad Khuroo,Nand Kumar,Tausif Monif,Manoj S Tomar

doi:10.1155/2009/748492

Abstract

The aim of this study is to compare the single-dose oral bioavailability of memantine hydrochloride 10 mg tablets of Ranbaxy Laboratories Limited, with NAMENDA™ tablets (containing memantine hydrochloride 10 mg) of Forest Pharmaceuticals Inc. in healthy, adult, human subjects under fasting condition. The study was carried out as 2-way crossover design on 8 subjects in fasting and fed conditions. The plasma samples were obtained over a 72 h post dose in each period. Plasma memantine samples were analyzed by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) with positive ion electro spray ionization using multiple reactions monitoring (MRM). A sensitive, reproducible, accurate and validated LC-MS/MS method with limit of quantification (LOQ) 0.200 ng/mL was used to analyze memantine. Ln transformed AUC0-72and Cmaxwere assessed for bioequivalence using 90% confidence interval (CI). 90% confidence intervals for the ratio of test and reference (Ratio of least-squares mean) for ln-transformed AUC0-72and Cmaxwere within the regulatory acceptance criteria of 80-125%.

Highlights

Memantine, an amantadine derivative, chemically 3,5-dimethyladamantan-1-amine is a moderate-affinity, uncompetitive, voltage-dependent, NMDA-receptor antagonist with fast on/off kinetics that inhibits excessive calcium influx induced by chronic over stimulation of the NMDA receptor
It is generally accepted that the standard equivalence range for basic pharmacokinetic characteristics such as AUC0-72 and Cmax is 0.80-1.25
Memantine hydrochloride 10 mg tablet developed by Ranbaxy Laboratories Limited, India is bioequivalent to namenda 10 mg tablets Forest Pharmaceuticals Inc., subsidiary of forest Laboratories, Inc

Summary

Introduction

An amantadine derivative, chemically 3,5-dimethyladamantan-1-amine is a moderate-affinity, uncompetitive, voltage-dependent, NMDA-receptor antagonist with fast on/off kinetics that inhibits excessive calcium influx induced by chronic over stimulation of the NMDA receptor. Memantine is indicated for the treatment of patients with moderate to severe dementia of the Alzheimer’s type[1]. Memantine showed low to negligible affinity for GABA, benzodiazepine, dopamine, adrenergic, histamine and glycine receptors and for voltage-dependent Ca2+, Na+ or K+ channels. Memantine showed antagonistic effects at the 5HT3 receptor with a potency similar to that for the NMDA receptor and blocked nicotinic acetylcholine receptors with one-sixth to one-tenth the potency[2]. Memantine generally modified the progressive symptomatic decline in global status, cognition, function and behavior exhibited by patients with moderate to severe Alzheimer’s disease[3]. The mean volume of distribution of memantine is 9-11 L/kg and the plasma protein binding is low (45%)

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