**1.3 Pharmacokinetic of methadone**

The pharmacokinetic parameters of methadone were first published in 1975 (Verebely *et al*, 1975). Methadone is a lipophilic basic drug with a pKa of 9.2, which is administered orally in a racemic mixture. There is strong evidence that the enantiomers differ in their distribution and elimination, though the majority of the studies were carried out on the racemic mixture. It has been suggested that methadone undergoes adaptive changes during chronic use according to the administered doses.

Fig. 1.1. Methadone, (*RS*)-6-(Dimethylamino)-4,4-diphenylheptan-3-one

Several attributes have been suggested such as clearance and *CYP3A4*. Accordingly, several pharmacokinetic studies have been carried out to investigate whether therapeutic drug monitoring (TDM) is effective as a clinical endpoint, on the one hand, and to study the methadone kinetic profile, on the other. There has been suggestive evidence to nonfrequently monitor the kinetic of methadone to explain some unpredicted clinical response (Loimer and Schmid, 1992; Schmidt *et al*, 1993; Wolff and Hay, 1994; de Vos *et al*, 1996). It may be useful especially when all other measures have been taken adequately and a patient still cannot hold on methadone with high doses.

It should be noted that methadone Cp cannot be used directly to describe the clinical response, as a certain time is required for the drug to distribute adequately in the nervous system. Thus, some researchers have suggested the use of an effect-compartment or linkmodel to describe the effect appropriately (Ekblom *et al*, 1993). So far, only four studies have modeled methadone by this approach and only one among them for MMT patients (Dyer *et al*, 1999). It was noticed that there is an inverse relationship between plasma concentrations and withdrawal scores and pupil diameters. On the other hand, there was a direct relationship between plasma concentrations and pain threshold in the same patients. The area under the curve did not differ between those who reported withdrawal symptoms and those who did not. The study suggested that there is correlation between methadone clinical responses and changes in the plasma levels for methadone racemic mixture.
