CYP2D6 and DRD2 genes differentially impact pharmacodynamic sensitivity and time course of prolactin response to perphenazine.

Objectives: We observed that CYP2D6 contributes to pharmacodynamic tissue sensitivity to perphenazine as measured by the areas under the curve (AUCs) expressed as a ratio (prolactin-AUC0-6/perphenazine-AUC0-6) in Chinese Canadians [Pharmacogenetics and Genomics 2007; 17:339-347]. As genetic heterogeneity in drug targets can influence drug response, we sought to further evaluate the contribution of CYP2D6 to pharmacodynamic sensitivity in our previous study sample in tandem with DRD2, the primary molecular target for perphenazine.

Methods: Genotyping for DRD2 Taq1A, -141C ins/del and Ser311Cys functional polymorphisms was performed using PCR-restriction-fragment length polymorphism methods.

CYP2D6 genotype in relation to perphenazine concentration and pituitary pharmacodynamic tissue sensitivity in Asians: CYP2D6-serotonin-dopamine crosstalk revisited.

Objectives: Hyperprolactinemia is a common side effect of first-generation antipsychotics mediated by antagonism of dopaminergic neurotransmission in the pituitary. Most first-generation antipsychotics are metabolized by CYP2D6 in the liver. Further, CYP2D6 is expressed in the human brain as a 5-methoxyindolethylamine O-demethylase potentially contributing to regeneration of serotonin from 5-methoxytryptamine.

Pharmacogenomics: historical perspective and current status.

Pharmacogenomics is an extension of pharmacogenetics, a science described here in terms of five stages of development: 1) some clinical observations predicted genetic alterations of drug response; 2) additional case discoveries led to the term "pharmacogenetics," a concept broadened by 3) many systemic case studies, and the realization of its wide applicability; 4) came the recognition of systematic pharmacogenetic differences between human populations. Then it became clear that 5) most human drug-response differences were multifactorial, caused by many genetic alterations plus environmental factors. The recognition of these complexities, and the advance of genetics into genomics led to the broader science of pharmacogenomics.

A pharmacogeneticist's look at drug effects and the drug development process: an overview.

This paper describes the functional roles of the closely related pharmacogenetic and pharmacogenomic sciences in medicine. Firstly, they provide means for a better understanding of the function of drugs, and particularly of the differences of drug action between individuals and also between racially categorised populations. Secondly, they are repeatedly used during the long process of new drug development; the developer needs several patient contacts.

Human pharmacogenomics: the development of a science.

Until about 50 years ago, the altering of a normal drug effect by a genetic deficiency was only rarely observed. Here, my discovery of the genetic variant of butyrylcholinesterase affecting succinylcholine action is described in some detail. Such discoveries led to the combination of the two older sciences, genetics and pharmacology, thereby forming pharmacogenetics.

Pharmacogenetics and personalised medicine.

The traditional concern of pharmacogenetics was Mendelian (monogenic) variation, which visibly affected some drug responses. Pharmacogenetics was broadened by the observation that multifactorial genetic influences, in conjunction with environmental factors, usually determine drug responses. Variability of gene expression, a new theme of the science of genetics, also affects pharmacogenetics; for example, enhanced enzyme activity does not necessarily indicate a mutation, but may be the consequence of a drug-induced enhancement of gene expression.

Modeling of human hepatic CYP3A4 enzyme kinetics, protein, and mRNA indicates deviation from log-normal distribution in CYP3A4 gene expression.

Aims: To determine whether the variability in cytochrome P(450) (CYP)3A4 metabolic function is exhibited at both transcription and translation levels and to examine the population distribution of CYP3A4 enzyme kinetics, protein, and mRNA.

Methods: Enzyme kinetics of testosterone 6beta-hydroxylation, immunoblot CYP3A4 protein, and CYP3A4 mRNA were determined in a microsomal bank of human livers. The distribution of these determinations was analyzed using cumulative distribution (probit) plots and normality test variable (NTV) to detect deviation from normality.