High impact information on l-Methadone

• RESULTS: CYP2B6 genotype influences (S)-methadone and, to a lesser extent, (R)-methadone plasma levels, with the median trough (S)-methadone plasma levels being 105, 122, and 209 ng . kg/mL . mg for the noncarriers of allele *6, heterozygous carriers, and homozygous carriers (*6/*6), respectively (P = .0004) [1].
• CONCLUSIONS: The disposition of the active enantiomer, R -methadone, can be predicted in part by CYP3A activity and protein binding to alpha1-AGP (ORM2), whereas S-methadone disposition is not well explained by the factors examined in this study [2].
• S-Methadone showed an idiosyncratic distribution with largely unpredictable pharmacokinetics [2].
• CONCLUSIONS: (R)- and (S)-methadone are substrates of P-gp [3].
• RESULTS: Plasma concentrations of (R)- and (S)-methadone were similar between the two animal groups [3].

Biological context of l-Methadone

• METHODS: The kinetics of 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) formation via N-demethylation of rac-, (R)- and (S)-methadone in human liver microsomes prepared from six liver samples were determined by h.p.l.c., and inhibition of metabolic function was studied using isoform-specific chemical inhibitors and monoclonal antibodies [4].
• R- and S-methadone were quantified by h.p.l.c. The areas under the plasma and milk concentration-time curves (AUC) were estimated and M/P(AUC) was calculated [5].
• At the mu2 receptor, the IC50 value of R-methadone was 6.9 nM and 88 nM for S-methadone, respectively [6].
• Bioequivalence testing was conducted of total, R-, and S-methadone area under the serum or plasma concentration-time curve during the 24-hour dosing interval at steady state (AUCss) and maximum concentration in serum or plasma (Cmax) [7].

Anatomical context of l-Methadone

• The P-gp in BBB greatly limits the brain entry of (R)- and (S)-methadone to their central nervous system acting sites [3].
• Distribution of R- and S-methadone into human milk during multiple, medium to high oral dosing [5].

Associations of l-Methadone with other chemical compounds

• AIMS: To investigate within- and between-subject variability of the pharmacodynamics and pharmacokinetics of (R)- and (S)-methadone in methadone maintenance subjects at steady-state [8].
• However, inhibition of the metabolism of (R)- and (S)-methadone by paroxetine was due to inhibition not only of CYP2D6, but also CYP3A4 and, to a minor extent, CYP2C8 [9].
• Effect of tenofovir disoproxil fumarate on the pharmacokinetics and pharmacodynamics of total, R-, and S-methadone [7].

Gene context of l-Methadone

• Expressed CYP3A4 and CYP2C19 showed similar reaction rates for both (R)- and (S)-methadone, while CYP2D6 did not catalyse this reaction [4].
• CONCLUSION: Although CYP2B6 influences (S)-methadone plasma levels, given that only (R)-methadone contributes to the opioid effect of this drug, a major influence of CYP2B6 genotype on response to treatment is unlikely and has not been shown in this study [1].
• But for the metabolism of (S)-methadone, the roles of CYP2C8 and CYP3A4 appeared equal [9].
• To clarify the oxidative metabolism of methadone (R)- and (S)-enantiomers, the depletion of parent (R)- and (S)-methadone and the formation of racemic 2-ethylidene-1,5-dimethyl-3,3-diphe-nylpyrolidine were studied using human liver microsomes and recombinant cytochrome P450 enzymes [9].

Analytical, diagnostic and therapeutic context of l-Methadone

• In addition, unbound (R)- and (S)-methadone concentrations were measured in plasma samples by ultrafiltration [10].
• Whole blood (R)- and (S)-methadone concentrations were measured using stereoselective HPLC [11].
• In stark contrast to analgesia, in vivo (S)-(+)-methadone caused significantly greater inhibition of basal proliferation (P<0.001, -130%) than (R)-(--)- and racemic methadone [12].

References