Mexiletine -enantiomers

K. M. McErlane, L. Igwemezie, and C. R. Kerr, Stereoselective serum protein binding of mexiletine enantiomers in man. Res. Commun. Chem. Pathy. Pharmacy., 56 141 (1987). 

VL Lanchote, PS Bonato, SA Dreossi, PV Goncalves, EJ Cesarino, C Bertucci. High-performance liquid chromatographic determination of mexiletine enantiomers in plasma using direct and indirect enantioselective separations. J Chromatogr B 685 281-289, 1996. 

In more recent studies, Turgeon and colleagues have reported the effects of coadministration of caffeine [131] or propafenone [132] on the stereoselective pharmacokinetics of mexiletine in poor and extensive metabolizers of debrisoquine. Caffeine, a substrate for CYP1A2, did not significantly change the plasma eoncentrations of mexiletine enantiomers in either PMs or EMs [131]. However, it resulted in a slight decrease ( 15%) in the urinary recovery of N-hydroxymexiletine generated from the R enantiomer in both EMs and PMs [131]. The metabolism of the S enantiomer was not affected because the N-hydroxymexiletine recovered in urine is mostly from the R enantiomer. 

In contrast to caffeine, propafenone coadministration significantly reduced the metabolism of both enantiomers of mexiletine in EMs [132]. However, it did not have a significant effect on the pharmacokinetics of mexiletine enantiomers in PMs. In fact, after coadministration of propafenone to EMs, the plasma concentration-time profiles and pharmacokinetics of mexiletine enantiomers in these subjects were not distinguishable from those in PMs [132]. These results are in agreement with the inhibitory effects of propafenone on the CYP2D6 pathway and are similar to those obtained with quinidine, another CYP2D6 inhibitor (Table 13). 

Turgeon, J. Uprichard, A.C. Belanger, P.M. Harron,D.W. Grech-Belanger,0. Resolution and electrophysiological effects of mexiletine enantiomers. J. Pharm. Pharmacol. 1991, 43, 630-635. 

De Luca, A. Natuzzi, F. Lentini, G. Franchini, C. Tortorella, V. Conte Camerino, D. Stereoselective effects of mexiletine enantiomers on sodium currents and excitability characteristics of adult skeletal muscle fibers. Naun5m. Schmiedebergs Arch. Pharmacol. 1995, 352, 653-661. 

Kwok, D.W. Kerr, C.R. McErlane, K.M. Pharmacokinetics of mexiletine enantiomers in healthy human subjects. A study of the in vivo serum protein binding, salivary excretion and red blood cell distribution of the enantiomers. Xenobiotica 1995, 25, 1127-1142. 

Mexiletine contains an amino group, and at pH 7, it exists as its conjugate acid that is the amino group is a protonated ammonium ion. When a solution of ( )-mexiletine at pH 7 passes through a column whose chiral hgand is (5)-aspartate, ion pairs between the chiral column matrix and the (+) and (-) forms of mexiletine form transiently. The ion pairs are diastereomers, and the mexiletine enantiomers do not have the same affinity for the column. It turns out that (—)-(i )-mexiletine binds to the column with lower affinity than its enantiomer, and it emerges from the column (elutes) first. A complete separation of enantiomers is the result. 

This report presents various methods developed primarily at our laboratory for chromatographic resolution of racemates of several pharmaceuticals (e.g., -blockers, NSAIDS, anta-acids, DL-amino acids, Bupropion, Baclofen, Etodolac, Carnitine, Mexiletine). Recently, we developed methods for establishing molecular dissymmetry and determining absolute configuration of diastereomers (and thus the enantiomers) of (/< .S )-Baclofcn, (/d.SJ-Bctaxolol with complimentary application of TLC, HPLC, H NMR, LCMS this ensured the success of diastereomeric synthesis and the reliability of enantioseparation. 

One of the most commonly used class of derivatization agents for diasteromer formation are isothiocyanates and isocyanates. Enantiomers of /3-blockers, amphetamine, epinephrine, methamphetamine, and mexiletine have been resolved after derivatization with these agents. Isothiocyanates produce thiourea derivatives upon reaction with primary and secondary amines. Thiourea derivatives also provide a strong UV absorbance for the detection of enantiomers lacking a strong UV chromophore. Isocyanates produce ureas when reacted with amines. The physical properties of these ureas are similar to thiourea derivatives. Isocyanates will also react with alcohols to yield carbamates. 

Mexiletine also suppresses the a toxin-modified action potentials, with IC50S equal to 1 mM for the peak and 4—6 /t M for the area-under-the-plateau, both indistinguishably different between enantiomers. Half-inhibition of the first oscillation after the peak occurred at 50-60 /iM. 5 M and 25—30 /zM R-M, whilst the second oscillation s amplitude was halved by e. 40 /iM A M and 20/iM R-M. 

FIG. 5. Use-dependent inhibition of fast Na" current in GH-3 cells. (A) Tonically inhibited current (measured at 0.1 Hz frequency) is further decreased, to a new steady-state, by a train of 20,1 s long depolarizations to 0 mV applied at 10 Hz. (B) Mexiletine s concentration-dependent role in steady-state use-dependent inhibition is shown by binding curves with inhibitory dissociation constants (Kj) that differ fourfold between enantiomers. Cumulative, endogenous slow inactivation accounts for the 15-20% reduction of current observed at 10 Hz without drugs. (C) The steady-state inhibition by M reached at 10 Hz stimulation frequency is still further potentiated when the potential between depolarizations is held at — 60 mV. 

Tocainide and mexiletine also show stereoselectivity in their action with the R(—) enantiomers being four and two times, respectively, more potent than their antipodes in sodium channel blocking activity (Table 8). In contrast, there is no stereoselectivity in the main antiarrhythmic action of encainide, flecainide, and propafenone (Table 8). 

The fact that the metabolism of mexiletine cosegregates with debrisoquine hydroxylation was not known until recently [112]. Initial studies [129,130] on the stereoselective pharmacokinetics of mexiletine did not distinguish between poor and extensive metabolizers of debrisoquine in their study subjects (Table 13). These studies showed modest or no stereoselectivity in the systemic clearance, the renal clearance, and the terminal plasma half-life of the drug [129,130]. In 1993, Turgeon and colleagues [112] reported the kinetics of the individual enantiomers of mexiletine after a single dose of the racemate in 10 EMs and 4 PMs in the absence and presence of steady-state... 

We will examine the separation of the enantiomers of mexiletine, an antiarrhythmic drug that acts by blocking sodium channels. (—l- -mexiletine is far more potent than its enantiomer, but for a long time, mexiletine has been administered as a racemic mixtme. In many cases, if one enantiomer of a drug is effective therapeutically, its enantiomer is either inactive or toxic. Thus, the... 

Deracemizatlon of racemic mexiletine (di-o-methyl-phenoxyisopropylamine) is successfully achieved in a simple two-step procedure. This work extends the utility of the TA to include deracemizatlon of amines and the asymmetric synthesis of ketones to bypass the limitations of kinetic resolution. The cofactor is recycled by amino acid oxidase [73] in the first deracemizatlon step and by dehydrogenases in the second asymmetric synthesis step [47a,74]. In addition, both enantiomers of mexiletine can be obtained by simply switching the order of the addition of stereospecific TAs. 

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