Methadone, enantiomers

Racemic methadone (MET) is administered to heroin addicts as a substitution therapy. However, methadone enantiomers possess different pharmacological effects, and the drug has been demonstrated to be enantioselectively metabolized to its two major metabolites, 2-ethylidene-l,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and 2-ethyl-5-methyl-3,3-diphenyl-l-pyrroline (EMDP). Stereoselective separation of MET, EDDP, and EMDP using an alpha-glycoprotein stationary phase and MS-MS detection was proposed by Kelly et al. [34]. Optimal separation conditions were 20 mM acetic acid isopropanol (93 7, pH 7.4), with a flow rate of 0.9mL/min. 

The concentration of AGP in the plasma of healthy volunteers correlated significantly with the binding ratio (bound/free) of the enantiomers, as well as the racemic form, of methadone. The average free fractions for +)- and (—)-methadone in plasma were 0.100 and 0.142, respectively (97). Two variants of AGP, orosomucoids 2A and FI, were also found to play important determining roles in the binding of methadone enantiomers (97). The authors of the study point out that the levels of AGP variants should be considered in protein binding studies. 

M, Huttemann H, Baumann P, Eap CB (2005) Methadone enantiomer plasma levels, CYP2B6, CYP2C19, and CYP2C9 genotypes, and response to treatment. Clin Pharmacol Ther 78 593-604... 

Hendrix, C. W., Wakeford, J., Wire, M. B., Lou, Y., Bigelow, G. E., Martinez, E., Christopher, J., Fuchs, E. J., and Snidow, J. W. (2004) Pharmacokinetics and pharmacodynamics of methadone enantiomers after coadministration with amprenavir in opioid-dependent subjects. Pharmacotherapy 24,1110-1121. 

Hendrix CW, Wakeford J, Wire MB, Lou Y, Bigelow GE, Martinez E, Christopher J, Fuchs EJ, Snidow JW. Pharmacokinetics and pharmacod3fnamics of methadone enantiomers after coadministration widi amprenavir in opioid-dependent subjects. Pharmacoffterapy (2004) 24,1110-21. 

Esteban J, de la Cruz Pellin M, Gimeno C, Barril J, Gimenez J, Mora E, Garcia-Perez AG. Increase of R-/S-methadone enantiomer concentration ratio in serum of patients treated with either nevirapine or efavirenz. Drug Metab Lett 2008 2(4) 269-74. 

Figure 24 shows the ternary phase diagram (solubility isotherm) of an unsolvated conglomerate that consists of physical mixtures of the two enantiomers that are capable of forming a racemic eutectic mixture. It corresponds to an isothermal (horizontal) cross section of the three-dimensional diagram shown in Fig. 21. Examples include A-acetyl-leucine in acetone, adrenaline in water, and methadone in water (each at 25°C) [141].

This s)mthetic opiate was introduced in 1965 to manage opioid dependence and has been successfully used as an aid to abstinence since that time. Methadone is a racemate, the R-enantiomer being the pharmacologically active form of the drug. This isomer shows a 10-fold higher affinity for the... 

Benmebarek M, Devaud C, Gex-Fabry M, et al. Effects of grapefruit juice on the pharmacokinetics of the enantiomers of methadone. Clin Pharmacol Ther 2004 76(l) 55-63. 

Opioid receptor binding Levomethadone is the more potent and p-selective levo-enantiomer of racemic methadone (Sim, 1973). It has an opioid receptor affinity in the range of morphine. 

Analgesic efficacy and clinical use Levomethadone like racemic methadone is a potent and long-acting opioid analgesic and can be used for the treatment of moderate to severe pain (Jamison, 2000 Davis and Walsh, 2001). It has an action profile similar to morphine and has significant antitussive properties, for which it is used in terminal lung cancer. The long duration of action makes the compound suitable for substitution treatment of opioid addiction (Joseph et al., 2000 Pallenbach, 2002). For practical and economic reasons the racemate instead of the levo-enantiomer is used in addicts. 

Rosas, M.E., K.L. Preston, D.H. Epstein, E.T. Moolchan, et al., Quantitative determination of the enantiomers of methadone and its metabolite (EDDP) in human saliva by enantioselective liquid chromatography with mass spectrometric detection, J. Chromatogr. B Anal. Technol. Biomed. Life Sci., 796(2), 355-370, 2003. 

Synthesis of single-enantiomer methadones has also been achieved using the chiral pool approach. Thus, Barnett and Smirz obtained ( )-(+)-l-dimethylamino-2-propanol (18) from (-)-... 

This procedure has beert used to obtain both enantiomers of methadone, where approximately 50% total yield of enantiomerically pure material can be obtained [37],... 

Following a report of withdrawal symptoms in three patients taking methadone maintenance therapy, serum methadone concentrations were measured before and after starting efavirenz in one patient (26). Serum methadone concentrations were as follows (R)-methadone (the active enantiomer) 168 ng/ml and 90 ng/ml before and after efavirenz. The corresponding (5)-methadone concentrations were 100 and 28 ng/ml. The dosage of methadone was increased from 100 to 180 mg/day before the patient s withdrawal symptoms resolved. 

Methadone and its isomer isomethadone (140,Fig. 7.29), which was also obtained from early syntheses of methadone (see Ref 463), each contain an asymmetric center. The more active isomers for both compoundsarethe (-) isomers (seeRefs. 284,463). The (-) enantiomer of methadone, which has the R configuration, has 7-50 times higher potency in antinociceptive assays and greater than 10-fold higher affinity for opioid receptors than that of... 

Electrophoretic methods are widely used alternatives for the analytical determination of the enantiomeric purity of chiral compounds [194]. Due to the high elTi-ciency of capillary electrophoresis, separations can be achieved even when very low selectivities are observed. At a preparative scale, these methods are well established for the purification of proteins and cells [195] but there is very little published on enantioselective separations. Only recently, some interest in chiral preparative applications has been manifested. Separation of the enantiomers ofterbu-taline [196] and piperoxan [197] have been reported by classical gel electrophoresis using sulfated cyclodextrin as a chiral additive, while the separation of the enantiomers of methadone could be successfully achieved by using free-fluid isotachophoresis [198] and by applying a process called interval-flow electrophoresis [199]. 

The levo isomers of 3-hydroxy-7V-methyl-morphinan and of methadone are demethylated by rat hver 2-3 times more rapidly than the corresponding dextro antipodes. The S(+)-enantiomer of hexobarbital (Figure 26.4) is metabohzed almost twice as rapidly as the R(-)-enantiomer by allylic hydroxylation and, in the dog, the dextrorotatory isomer of 5-ethyl-5-phenyl-hydantoin affords 10 times more para-hydroxy-metabolite than the levorotatory isomer. ° Hydroxylation takes place alpha to a carbonyl in the dextrorotary enantiomer of glutethimide whereas the levorotamer is hydroxylated on the methylene group of the ethyl side chain. Numerous other examples are found in the literature. ... 

Methadone (Levomethadone, 6-dimethylamino-4,4-diphenylheptan-3-one) [125-58-6] M 309.4, m 98-100", [a] -32" (c 1.8, EtOH), see below for pKa. This pharmacologically active (against narcotic addiction) enantiomer was obtained by optical resolution (using D-tartaric acid) of the racemate and was purified by precipitation of the hydrochloride from aqueous solution at pH >6, dried and recrystalhsed from propan-2-ol. TheR-hydrochloride [5967-73-7], when recrystaUised from propan-2-ol, has m 245-246°, [a] -169° (c 2, EtOH). The S- +)-enantiomer [5653-8-5] also recrystaUises from propan-2-ol and has recorded m of 100-101°, [a] + 26° (c 1.2, H2O). The S-hydrochloride [15284-15-8], when crystallised from propan-2-ol, has m 243-244°, [a] h-169° (c 2, EtOH). [Larsen et al. J Am Chem Soc 70 4194 1948,... 

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