Huge individual variations in the activities of these enzymes have long been demonstrated, much of which have been accounted for with specific allelic variations in the genes encoding these enzymes. For example, CYP2D6 allelic profiles determine whether a particular individual is a poor metabolizer (those with defective genes encoding no enzyme; approximately 2% in Han LDN-193189 mouse Chinese and 7% in Caucasians), intermediate metabolizer (those with “less effective” gene; approximately

50% in East Asians), extensive metabolizer (those with “wildtype” alleles; approximately 47% in Inhibitors,research,lifescience,medical East Asians) and ultrarapid metabolizer (those with gene duplication or multiplication; about 1% in East Asians and Northern Europeans, but up to 7% in Spaniards and up to 30% in Arabs and Ethiopians).10 Studies involving desipramine and venlafaxine clearly indicate that these CYP2D6 polymorphisms are mainly responsible for the pharmacokinetics, dosing, and side-effect profiles of these CYP2D6 substrates.11,12 Similarly, specific allelic alterations Inhibitors,research,lifescience,medical also have been demonstrated to determine CYP2C19 enzyme activities, and consequently

the dosing and side effect profiles of medications metabolized by this enzyme. In addition, the activity of some of these CYPs also could be significantly altered by exposure to environmental agents, whose mechanisms also have been elucidated. For example, the induction Inhibitors,research,lifescience,medical effect of St John’s wort (and other natural substances) on CYP3A4 is now known to be mediated via the steroid and xenobiotic receptor fSXR], and Inhibitors,research,lifescience,medical the induction of CYP1A2 by constituents of cigarettes is mediated through the activation of the Ah receptor.13

Although less well documented, a number of genes other than the CYPs also influence the process of pharmacokinetics, and thus are likely to also affect the dosing and side-effect profiles of ADs. These include genes encoding transferases, such as glutathione-S-transf erase (GST) and UDP-glucurunosyltransferases (UGTs), which are responsible for drug conjugation; multldrug-resistance Inhibitors,research,lifescience,medical gene (MDR1) encoding the P-glycoprotein responsible for exporting lipophilic compounds to the extracellular space (and thus reducing drug absorption in the gut as well as inhibiting their crossing the blood-brain barrier)14,15; and, Calpain orosomucoid 1 and 2 (ORM1 and ORM2) encoding the alpha-1-acid glycoproteins responsible for most of the often extensive binding of psychotropics to plasma proteins.16,17 (Table I) Table I. Candidate genes and corresponding single nucleotide polymorphism (SNP) densities (pharmacokinetics). Genes encoding therapeutic targets of ADs (pharmacodynamics) A number of monoamine neurotransmitter systems, including serotonin (5-HT), norepinephrine (NE), and dopamine (DA), may all play crucial roles in mediating vulnerability to depressive disorders.