**3.3.2.2 PK-PD model**

Clozapine and Olanzapine are extensively metabolized in the liver, via the cytochrome P450 system, to polar metabolites suitable for its elimination in the urine and faeces. The CYP1A2 isoenzyme is primarily responsible for metabolism of Clozapine and Olanzapine , but another CYP`s seems to play a role, as well. Inducers agents, e.g. cigarette smoke, or inhibitor agents, e.g. Theophylline, Ciprofloxacin, Fluvoxamine, of the CYP1A2 may increase or decrease, respectively, the metabolism of Clozapine and Olanzapine. For example, the induction of metabolism caused by smoking means, that smokers would require double up the dose of Clozapine and/or Olanzapine compared with non-smokers ir order to achieve an equivalent plasma concentration (Entrez Gene 2011).

#### **3.3.2.3 PD-PG model**

The poblational analysis of plasma cortisol levels, using Kernel`s test , allow us to detect 2 populations, sex-linked and related to an alterations of the dopaminergic and/or serotonergic, caused by a combination of the different polymorphisms of genes encoding SERT and 5-HT2a receptor, among others, obtaining from the application of the equation 2, the following equi-effective dose ratio:

$$\frac{\text{DOSE} \left(\text{genotype} : \text{wid type}\right)}{\text{DOSE} \left(\text{genotype} : \text{polimorhicic type}\right)} = 2 \text{ or } 4$$

in dependence of the variant alleles present (Lozano et al 2008a, 2010c).
