**3.4 Methadone**

The reduction of the testosterone levels induced by drugs with opioid activity, seems to be receptor mediated, since the different isomers have different activities: the levorotatory isomers are much more effective than dextrorotatory isomers (Cicero et al 1974, 1975, 1976, 1977; Mendelson et al 1976).

There are many different studies showing that the relative potency of drugs to reduce serum testosterone levels is parallel to its analgesic activity and its affinity for opioid receptors in the brain. So, this ability to decrease plasma testosterone and/or urine can be used as a trial to evaluate the structure-activity relationship, kinetic constants of association-dissociation to receptors, and reach conclusions about their pharmacological potency and its optimal therapeutic dose (Cicero et al 1975, Mendelson et al 1976).

Biomarkers and Therapeutic Drug Monitoring in Psychiatry 169

*Ltg Bil o MM*

*Inh Ltg M M*

*EKK* 

*Bil*

(6)

*Inh K* (7)

 2

allowing us to conclude that the main factors affecting Cp of Lamotrigine are the amount of UGT enzyme (Eo) and KM values of inhibitors with respect to those of Lamotrigine and

> 

*Ltg K*

This method described above allows the analysis of the main factors affecting competitive inhibition between two substrates, such as: UGT enzyme concentration, exponentially, and

Is based on individual genetic polymorphisms which can alter the enzymatic activity of UGT1A1: The enzyme that conjugates bilirubin is called uridindifosfoglucuronato glucuronosyltransferase,UGT, and its production is regulated by a promoter that can have a mutation that causes decreased production of this enzyme. The amounts of UGT, in Gilbert's syndrome, are reduced until 30% of the normal value. The genetic defect is in the insertion of an extra base pair in the promoter TATA box in the gene encoding the enzyme UGT and that is located on chromosome 2 (Bosma et al 1995). Gilbert's syndrome, therefore, is a disease in which there is a high bilirubin level and the values in these patients ranging between 20 mmol/dl and 80 mmol/dl, obtaining from the application of the equation 6, the

> DOSE genotype : wild type <sup>2</sup> DOSE genotype : Gilbert`s syndrome

The new generation of AEDs such as Topiramate, Oxcarbazepine, Gabapentin, and Levetiracetam, acts by enhancing GABAergic neurotransmission: The gamma-aminobutyric acid, GABA, has 2 types of receptors, A and B. When GABA binds to GABAA receptor, facilitates the passage of chlorine, negatively charged ion, inside the cell through chloride channels. This influx of chloride increases the negativity of the cell (ie, a resting potential more negative membrane) causing it a greater difficulty to reach the action potential resulting, finally, in a cell stabilization (Barnard et al 1998; Kravitz et al 1963; Krnjević & Schwartz 1967; Sieghart & Sperk 2002; Takeuchi & Onodera 1972; Takeuchi & Takeuchi

*Ltg*

(Eo = [UGT], KM = Michaelis-Menten Constant) (Bil= Bilirrubina, Ltg= Lamotrigina, Inh= Inhibidor)

Bilirubin, according to the following relation:

**3.5.1 PK-PG model** 

KM value of substrates (Lozano et al 2009a, 2009b, 2010d).

following equi-effective dose ratio for Lamotrigine:

(Lozano et al 2009a, 2009c, 2010d).

**3.6 New antiepileptics** 

1967, 1969).

The ability of opioid drugs to reduce serum testosterone levels, also, can be effectively used as a measure to assess the pharmacological activity of Methadone. Therefore, indirect assessment of the Methadone concentration in the biophase, can be accomplished by using the test of depletion of testosterone or test of depletion of LH that, also, seems to be specific for narcotic effect and correlates well with changes in testosterone levels (Kosterlitz & Warp 1968; Lozano et al 2008b, 2009b; Snyder 1975).
