
Peak serum concentration following a single oral dose of 15 mg was 0.075 mg/l; 0.86 mg/l for 100 mg, and 0.83 mg/l for 120 mg, all at 4 h [1] .
Plasma half-life of methadone averages 25 h.
The elimination is via kidney. The elimination is biphasic: initial elimination half-life is 12 to 24 h, followed by slower elimination half-life of 55 h [6] .
Plasma half-life of methadone averages 25 h.
Passage of blood-brain barrier: limited. Methadone penetrates through the placenta [6] .
Metabolism and excretion
Methadone is a synthetic narcotic drug metabolized in liver by mono-and di-Ndemethylation. Main metabolites are: 2-ethylidene-1,5-dimethyl-3,3-diphenyl pyrrolidine (EDDP, 3 to 25 %), 2-ethyl-5-methyl-3,3-diphenylpyrroline (EMDP), phydroxylated derivatives, glucuronide conjugated derivatives, methadol and normethadol. Most of these compounds are inactive metabolically [1, 7] .
Metabolism and excretion
In the liver, methadone undergoes biotransformation by the cytochrome P450. Both cytochrome P450 isoenzymes, CYP 3A4 and CYP 2D6, are involved in this process [8] .
Metabolism and excretion
Excretion: from 5 to 50% of ingested dose is excreted in urine as unchanged methadone over 24 h in maintenance subjects. Methadone is also excreted in feces, bile and sweat [7] .
Pharmacokinetic and toxicologic mechanisms
In similarity with other opiates (e.g. morphine, codein, heroin and oxycodone) methadone depresses nerve transmission in sensory pathways of the spinal cord and brain that signal pain. Opiates bind to mu (μ) receptors, and inhibit brain centers controlling coughing, breathing, and intestinal motility. When methadone is used instead of heroin, it occupies the same receptor and is a stabilizing factor that permits addicts on heroin to change their behavior and to discontinue heroin use (addiction to heroin is often replaced by addiction to methadone, which is much less severe).
Pharmacokinetic and toxicologic mechanisms
Methadone is an opioid antagonist of glutamate receptor N-methyl-D-aspartate (NMDA), which inhibits serotonin/norepinephrine reuptake. Blockade of NMDA receptor can decrease excitability and reduce seizure activity. NMDA receptor also has been implicated in heroin, cocaine, alcohol, and nicotine addiction [9] .
Pharmacokinetic and toxicologic mechanisms
The precise toxicological mechanism of methadone poisoning is still unknown. Methadone affects equilibrium of the neurotransmitters in the brain. In similarity with amphetamine and morphine, it stimulates the release of biogenic amines, such as norepinephrine and dopamine, from stores in adrenergic nerve terminals, which leads at the overdose to CNS depression and respiratory failure.
Pharmacokinetic and toxicologic mechanisms
Recent studies in animal models suggested that methadone may be a substrate of Pglycoprotein. The latter limits the entry of methadone to their CNS acting sites [6] .
Pharmacokinetic and toxicologic mechanisms
In cultured human hepatocytes, methadone inhibits synthesis of albumin and reduces the level of intracellular glutathione [10] .
Pharmacokinetic and toxicologic mechanisms
Target organs: CNS, lung.

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