These are partly based on functional genetic polymorphisms of the responsible genes. Pharmacokinetics, ie, the distribution

and metabolism of drugs, is dependent, on genetic variants of the metabolizing enzymes and transport proteins. Some of these are: The P450 cytochromes, which are members of the phase I metabolizing enzymes responsible for oxidation of functional groups. The phase II metabolizing enzyme N-acetyltransferase (NAT), which is responsible Inhibitors,research,lifescience,medical for the conjugation of substances with hydrophilic molecules for facilitated renal excretion. The multidrug resistance protein (MDR1), which controls the active transport, through the membranes of cells. These determine the plasma levels and also the spectrum of metabolites, and are thus responsible for the effects and side effects of drugs. In addition, psychotropic drugs interact, at this level and influence each Inhibitors,research,lifescience,medical other. Table I. Reasons for nonresponse

to treatment Cytochrome P450 enzymes Various cytochromes are responsible for the metabolism of psychotropic drugs,5 most, notably cytochromes CYP2C19, CYP3 A4, CYP1A2, and CYP2D6. Halopcridol, for example, is metabolized by CYP2D6, CYP3A4, and CYP1A2. Notably, the enzyme CYP2D6 exists in more than 20 different genetic Inhibitors,research,lifescience,medical variants, so-called polymorphisms, which show different enzymatic activities. Next, there are slow metabolizers, extensive metabolizers, and ultrarapid metabolizers. Several allelic variants of the CYP2D6 gene can lead to a nonfunctional enzyme or reduced CYP2D6 activity. The most Sirtuin inhibitor common mutations in Caucasians associated with a slow metabolizer phenotype are the CYP2D6*3*4*5*6 alleles, or combinations of these, Inhibitors,research,lifescience,medical leading to a nonfunctional enzyme or reduced activity when they occur as heterozygous combinations with the wild-type allele. The ultrarapid metabolizer CYP2D6 phenotype is associated with a gene duplication. Up to 13 CYP2D6 copies Inhibitors,research,lifescience,medical could be the result of this mutation.6 The extensive metabolizer phenotype

could therefore be a result, of a homozygeous CYP2D6 wild-type genotype or a combination of alleles coding for reduced or abundant activity (CYP2D6*3*4*5*6*10*17) and alleles Calpain coding for increased activity. In a study with haloperidol, which is degraded to reduced halopcridol, a pipcridine metobolite, and a presumably neurotoxic substance haloperidol pyridinium (HPP+) (Figure 3), we noted that patients with the allele CYP2D6*4, which exists in around 10% of the Caucasian population and determines a slow metabolizer, show higher plasma levels of haloperidol and reduced haloperidol. At the same time, these patients showed a poorer response to treatment and more side effects. CYP3A4 is responsible for the increased occurrence of the possibly neurotoxic metabolite HPP+,7,8 showing similarities to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridinium (MPTP), which provoked symptoms similar to Parkinson’s disease in heroin addicts.