Relationship with plasma concentrations was shown for drugs with dominant CYP2D6-mediated metabolism, but large intragenotypic variability tended to obscure its clinical value. However, there was no relationship reported for failure to respond beneficially. There was a general modest trend observed towards a positive

correlation between the genotype, especially the presence of *10 allele in the Japanese, and severity of TD and EPS. This discouraging finding is hardly surprising, since many antipsychotic agents are metabolized by multiple pathways and many have active metabolites. It is, however, acknowledged that these studies were highly heterogeneous, investigating a variety of drugs, Inhibitors,research,lifescience,medical regardless of the pharmacokinetics, pharmacodynamics, and pharmacokinetic/pharmacodynamic Inhibitors,research,lifescience,medical relationships of the drugs and their metabolites. Dahl has recently reviewed the relevance of CYP2D6 and other genetic polymorphisms of drug-metabolizing enzymes in

relation to clinical response to antipsychotic therapy,11 reaching essentially the same conclusion as this author. Another important area of interest in pharmacogenetics has focused on candidate genes of the pharmacological targets that play a role in susceptibility to TD. Four published studies have investigated an association between a Ser9Gly polymorphism in exon 1 of the dopamine D3 receptor gene (DRD3) Inhibitors,research,lifescience,medical and TD; three failed to show an association and one found an insignificant trend. Lerer et al19 examined this association in a pooled sample of 780 patients (317 Inhibitors,research,lifescience,medical with TD and 463 without TD). Their findings support a small but significant, contribution of the DRD3 Ser9Gly polymorphism to TD susceptibility, which is demonstrable over and above population effects

Inhibitors,research,lifescience,medical and the effect of age and gender on the phenotype. Arising from the globalization of drug development programs, the global heterogeneity in the frequencies of various variant alleles in different populations has become an important www.selleckchem.com/products/AP24534.html regulatory issue. The ICH guideline20 on “Ethnic Factors in the Acceptability of science Foreign Clinical Data” recommends evaluation of the clinical trials data from one region or population for their extrapolation to another region or population. To this end, it is recommended that the submission should include (i) adequate characterization of pharmacokinetics, pharmacodynamics, dose-response, efficacy, and safety in the population of the foreign region; and (ii) characterization of pharmacokinetics, pharmacodynamics, and dose-response in the new region. The guideline recognizes the role of genetic factors and the slope of the dose-response curve in determining whether the drug is likely to show significant ethnic differences during clinical use. When interethnic differences are anticipated, bridging studies may be required.