Molecular Modelling Analysis of the Metabolism of Methadone
Methadone (Met) is a synthetic opiate used for analgesis in patients and to treat opioid dependence. Maintenance treatment with Met has contributed to a drop in mortality, reduction in heroin use, decrease in criminal activity and improvement in social relationships, reduction in risk of HIV and hepatitis virus infection. Met is an opiate μ-receptor agonist. It is a chiral molecule that exists in (S)-Met and (R)-Met forms. Except in Germany, Met is therapeutically administered as a racemic mixture. (R)-Met has a higher affinity for the μ-opioid receptor and a longer plasma elimination half-life than (S)-Met. Met undergoes rapid metabolism almost exclusively in the liver by sequential N-demethylation followed by spontaneous cyclisation to form EDDP and EMDP followed by renal and faecal excretion. EDDP and EMDP do not display any analgesic activity. Cytochrome P450 enzymes CYP3AP, CYP2B6 and CYP2C19 are involved in the metabolism of methadone in human liver and intestine. After steady-state administration of Met, a large variation in the plasma (R)-Met to (S)-Met ratio is observed across a population suggesting that Met is metabolized stereoselectively in vivo. Whereas N-demethylation through CYP3AP is not stereo selective, CYP2B6 is found to metabolize (S)-methadone more rapidly than (R)-methadone while CYP2C19 does the reverse. Molecular modelling analyses show that the two enantiomers of methadone differ in their LUMO-HOMO energy separation and hence in their kinetic lability. In both the enantiomers, the centre of most negative electrostatic potential is found to lie close to the tertiary nitrogen, indicating that the position may be most susceptible to electrophilic attack.
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