Quantitation of the enantiomers of rimantadine and its hydroxylated metabolites in human plasma by gas chromatography/mass spectrometry

Choma, Nadia; Davis, Preston P.; Edom, Richard W.; Fukuda, Elaine K.

doi:10.1002/bmc.1130060105

Cited by 6 publications

(4 citation statements)

References 10 publications

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“…For example, although there are no significant differences in the concentration−time profiles and disposition of 2-R and 2-S and of the 3-hydroxyrimantadine metabolites, 37 large stereospecific differences in the disposition of their 4-hydroxyrimantadine metabolites are observed. 38 However, it should be noted that 3and 4-hydroxy metabolites, both of which are found in rimantadine-treated patients, showed only modest inhibitory activity against influenza A virus, i.e., they are modestly active metabolites. 39 ■ ASSOCIATED CONTENT * S Supporting Information…”

Section: Acs Medicinal Chemistry Lettersmentioning

confidence: 99%

Affinity of Rimantadine Enantiomers against Influenza A/M2 Protein Revisited

Drakopoulos

Tzitzoglaki

et al. 2017

ACS Med. Chem. Lett.

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Recent findings from solid state NMR (ssNMR) studies suggested that the (R)-enantiomer of rimantadine binds to the full M2 protein with higher affinity than the (S)-enantiomer. Intrigued by these findings, we applied functional assays, such as antiviral assay and electrophysiology (EP), to evaluate the binding affinity of rimantadine enantiomers to the M2 protein channel. Unexpectedly, no significant difference was found between the two enantiomers. Our experimental data based on the full M2 protein function were further supported by alchemical free energy calculations and isothermal titration calorimetry (ITC) allowing an evaluation of the binding affinity of rimantadine enantiomers to the M2TM pore. Both enantiomers have similar channel blockage, affinity, and antiviral potency.KEYWORDS: Rimantadine enantiomers, isothermal titration calorimetry, free energy perturbation, Bennett's acceptance ratio, electrophysiology, synthesis, antiviral assay, membrane protein, influenza M2 pore A mantadine (1) and rimantadine (2) (Scheme 1) are channel blockers of proton transit by the influenza virus M2 proton channel 1,2 and long used prophylactics and therapeutics against influenza A viruses. 3 The primary binding site of 1 and 2 is the lumen of the transmembrane domain of a tetrameric M2 protein (M2TM: amino acids 22−46) that forms the proton transit path. 4 Although 1 and 2 have been used as antivirals for decades, it was only after 2008 that high resolution structures from X-ray and ssNMR experiments unveiled the structures of M2TM in complex with 1 or 2. 5−9 According to these findings, the M2TM protein channel is blocked by 1 or 2 via a pore-binding mechanism. 6−10 The adamantane cage in 1 or 2, as well as in other aminoadamantane analogues, 11−13 is tightly contacted on all sides by V27 and A30 side chains, producing a steric occlusion of proton transit 6−9 and thereby preventing the viral replication. The ssNMR results for 2 also demonstrated that the ammonium group of the drug is pointing toward the four H37 residues at the C-terminus. 9 This orientation can be stabilized either through hydrogen bonds between the ammonium group of the aminoadamantane ligand and water molecules in the channel lumen which exist between the imidazoles of H37 and the ligand, 13 and/or with A30 carbonyls in the vicinity, 14 according to experimental 9,14−16 and MD simulations data. 13,17−22 Provided that M2TM is a minimal model for M2 binding, 10 these high resolution structures can be used for the development of new ligands which may bind more effectively to the M2TM pore.The effect of ligand's chirality in its binding with a chiral receptor is of outstanding significance and the characterization of protein−ligand interactions for each enantiomer separately may identify potential stereospecific binding interactions to the receptor. While rimantadine analogues are known antiviral drugs for more than four decades, the relative potency of rimantadine enantiomers has not been studied at the molecular level. The binding affinity...

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Section: Acs Medicinal Chemistry Lettersmentioning

confidence: 99%

Affinity of Rimantadine Enantiomers against Influenza A/M2 Protein Revisited

Drakopoulos

Tzitzoglaki

et al. 2017

ACS Med. Chem. Lett.

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“…A number of assays have been reported for the determination of rimantadine in biological fluids [6][7][8][9][10][11][12][13][14][15], including gas chromatography with electron-capture detection (GC-ECD) [6,7], gas chromatography with mass spectrometry (GC-MS) [8][9][10][11][12][13], high-performance liquid chromatography with fluorescence detection (HPLC-Flu) [14,15] and high-performance liquid chromatography with ultraviolet detection (HPLC-UV) [16]. The various experiments described above usually require complicated derivatization treatment and liquid-liquid extraction to increase its sensitivity, or special facilities for the use of radioactive compounds.…”

Section: Introductionmentioning

confidence: 99%

Determination of rimantadine in rat plasma by liquid chromatography/electrospray mass spectrometry and its application in a pharmacokinetic study

Xu¹,

Ju²,

Xia³

et al. 2008

Journal of Chromatography B

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“…HPLC, GC, etc.) coupled to either mass spectrometric detection or after derivatization prior to detection . Less demanding pharmaceutical quality control applications can be performed by batch spectrofluorimetry , near‐IR spectroscopy , and CE with simple indirect detection .…”

Section: Introductionmentioning

confidence: 99%

Determination of rimantadine in human urine by HPLC using a monolithic stationary phase and on-line post-column derivatization

2013

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In the present study, we propose the first HPLC method coupled to postcolumn derivatization for the determination of rimantadine in human urine samples. The analyte and amantadine (internal standard) were isocratically separated using an RP monolithic stationary phase (100 × 4.6 mm id) with a mobile phase consisting of CH3OH/phosphate buffer (25 mmol/L, pH 3.0) at a volume ratio of 50:50. Postcolumn derivatization involved on-line reaction with o-phthalaldehyde (20 mmol/L) and N-acetyl-cysteine (5 mmol/L) at alkaline medium (100 mmol/L borate pH 11.0). Spectrofluorimetric detection at λ(ex)/λ(em) = 340/455 nm enabled the selective and sensitive determination of rimantadine in urine samples at a range of 50-500 ng/mL with an LOD of 5 ng/mL. Human urine samples were analyzed successfully after SPE using hydrophilic-lipophilic balanced RP cartridges (30 mg/mL, Oasis HLB). Recoveries ranged between 89.7 and 102.7%.

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Quantitation of the enantiomers of rimantadine and its hydroxylated metabolites in human plasma by gas chromatography/mass spectrometry

Cited by 6 publications

References 10 publications

Affinity of Rimantadine Enantiomers against Influenza A/M2 Protein Revisited

Affinity of Rimantadine Enantiomers against Influenza A/M2 Protein Revisited

Determination of rimantadine in rat plasma by liquid chromatography/electrospray mass spectrometry and its application in a pharmacokinetic study

Determination of rimantadine in human urine by HPLC using a monolithic stationary phase and on-line post-column derivatization

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