Clinical pharmacokinetics and pharmacogenetics of tamoxifen and endoxifen

Introduction: Tamoxifen dominates the anti-estrogenic therapy in the early and metastatic breast cancer setting. Tamoxifen has a complex metabolism, being mainly metabolized by CYP2D6 into its 30–100 times more potent metabolite, endoxifen. Recently, a phase I study in which endoxifen as an orally z-endoxifen hydrochloride has been successfully evaluated.

Areas covered: the principal pharmacogenetic and non-genetic differences in the pharmacology of tamoxifen and endoxifen are evaluated. To this end, references from PubMed, Embase or Web of Science, among others, were reviewed As non-genetic factors, important differences and similarities such age, or adherence to tamoxifen therapy are comprehensively illustrated. Additionally, since CYP2D6 genotypes are considered the main limitation of tamoxifen, many studies have investigated the association between the worsened clinical outcomes in patients with non-functional CYP2D6 genotypes. In this review, an overview of the research on this field is presented. Also, a summary describing the literature about individualizing tamoxifen therapy with endoxifen concentrations and its limitations is listed.

Expert opinion: z-endoxifen hydrochloride is only investigated in the metastatic setting, still more research is required before its place in therapeutics is known. Similarly, monitoring tamoxifen efficacy based on endoxifen concentrations might not be overall recommended due to the limited evidence available.     

Prediction of phenotype for acetylation and for debrisoquine hydroxylation by DNA-tests in healthy human volunteers

Summary The debrisoquine/sparteine-type polymorphism of drug oxidation and the polymorphism for acetylation are two common inherited variations in human drug metabolism. The phenotypes for hydroxylation and acetylation can be predicted be newly developed methods based on mutation-specific amplification of DNA by the polymerase chain reaction (PCR), which also allow for identification of heterozygous carriers of one mutant allele.In the present study, the results of genotyping of 81 healthy European volunteers were compared with the phenotype obtained by the classical biochemical approach using debrisoquine and caffeine as probe drugs.Genotyping correctly predicted all 73 extensive metabolisers (EMs) and 6 out of 8 poor metabolisers (PMs) of debrisoquine. All 48 rapid acetylators and 33 of 35 slow acetylators were predicted.Overall, the DNA analysis result matched the in vivo phenotype in 97.5 % of individuals.     

Genetically determined N-acetylation and oxidation capacities in Japanese patients with non-occupational urinary bladder cancer

Summary Genetically determined polymorphisms of N-acetylation and oxidative capacity have been studied using dapsone and metoprolol in 51 Japanese patients with spontaneous bladder cancer and 203 healthy control subjects.The results for N-acetylation pharmacogenetics were against the initial expectation that there would be a preponderance of slow acetylators in the cancer group, as 3 such patients (5.9%) were found as compared to 13 (6.4%) in the healthy group. There was no poor metabolizer (PM) of metoprolol in the cancer group, whereas in the healthy group one (0.5%) was a PM. There were no significant differences between the groups in the frequency of slow acetylator and poor oxidiser phenotypes, or in the frequency distribution profiles of acetylation (monoacetyldapsone/dapsone) and oxidative metabolic ratio (log metoprolol/-hydroxymetoprolol).The results indicate that neither N-acetylation nor the debrisoquine/sparteine-type oxidative phenotype and/or capacity represent a genetic predisposition to spontaneous bladder carcinogenesis in Japanese patients. In the normal Japanese population there is a great predominance of rapid acetylators and extensive oxidisers.     

An Assessment of the Genetic Relationship Between Alcohol Metabolism and Alcoholism Risk in Australian Twins of European Ancestry

The present analyses examined genetic influences on alcohol metabolism and their possible relationship to risk of alcohol dependence. Subjects were 206 Australian twin pairs who participated in an alcohol challenge protocol in 1979–1981, in which they were given a 0.75 g/kg dose of alcohol; blood alcohol concentrations (BACs) measured at five times over a 3-hr period after alcohol ingestion were examined. Structural equation modeling, fitting a combined autoregressive and common factor model, indicated significant heritabilities for both men and women (h ² range = 0.19–0.71), with significant parameter heterogeneity as a function of gender. In 1992–1993, both twins from 159 of the alcohol challenge pairs completed a telephone-administered psychiatric diagnostic interview. Repeated-measures MANOVAs were used to examine whether respondent's or cotwin's DSM-III-R alcohol dependence status, or parental history of alcohol problems, was associated with variation in alcohol metabolism. There was some evidence that individuals at increased genetic risk of alcohol dependence [with either a paternal history of alcohol problems (women) or an MZ male cotwin who reported a history of alcohol dependence by 1992–1993] showed lower initial BACs than other groups. However, this effect was not seen in those who themselves had a history of alcohol dependence by interview follow-up, perhaps because this relationship was already masked by a history of excessive drinking at baseline.     

CYP2D6 genotyping strategy based on gene copy number determination by TaqMan real-time PCR

The genetic polymorphism of the cytochrome P450 monooxygenase, CYP2D6, comprises at least 43 alleles giving rise to distinct drug metabolism phenotypes termed ultrarapid, extensive, intermediate, and poor metabolizers. As a consequence, drug side effects or lack of drug effect may occur if standard doses are applied. Genetic prediction of drug oxidation phenotype as a basis for dose selection requires analysis of single nucleotide polymorphisms and of alleles with duplicated or deleted genes. Here we developed a novel method to determine the CYP2D6 gene dose per genome. A TaqMan real-time PCR assay to specifically amplify genomic CYP2D6 was established by using a specific set of amplification primers and probe, located in exon 9, which effectively prevent amplification of CYP2D7 and CYP2D8 pseudogenes. Quantitative CYP2D6 amplification data were normalized to albumin as an internal reference gene which was coamplified simultaneously in a single-tube biplex assay. The assay was validated with a selection of previously genotyped DNA samples containing none, one, two, or three CYP2D6 gene copies. The results were highly reproducible and closely matched the number of genes with no overlap between the groups. Analysis of DNA samples comprising all major alleles and genotypes revealed high sensitivity and specificity of the assay, as demonstrated by agreement of the determined gene dose with the presence of CYP2D6(*)2 x 2 (gene duplication) and CYP2D6(*) 5 (gene deletion) alleles. The predictability of the new strategy was systematically evaluated. The semiautomatic TaqMan assay allows high sample throughput and will be useful for pharmacogenetic studies and in the clinical setting.     

Specific immunotherapy safe and effective in childhood seasonal asthma

In the past 10 years, electronic health records (EHRs) have had growing impact in clinical care. EHRs efficiently capture and reuse clinical information, which can directly benefit patient care by guiding treatments and providing effective reminders for best practices. The increased adoption has also lead to more complex implementations, including robust, disease-specific tools, such as for rheumatoid arthritis (RA). In addition, the data collected through normal clinical care is also used in secondary research, helping to refine patient treatment for the future. Although few studies have directly demonstrated benefits for direct clinical care of RA, the opposite is true for EHR-based research – RA has been a particularly fertile ground for clinical and genomic research that have leveraged typically advanced informatics methods to accurately define RA populations. We discuss the clinical impact of EHRs in RA treatment and their impact on secondary research, and provide recommendations for improved utility in future EHR installations.     

Antenatal corticosteroid therapy: Current strategies and identifying mediators and markers for response

Landmark early work has led to the nearly universal use of antenatal corticosteroids to accelerate fetal lung maturity with pregnancies complicated by impending preterm birth. Antenatal corticosteroids clearly reduce respiratory morbidity, death, and other adverse neonatal outcomes. Limited pregnant human pharmacokinetic data and some animal data give clinicians some information as to the behavior of the drug in the body. However, there is controversy about the type, amount, and frequency of steroid to use for this therapy. This review article summarizes the history, clinical use, and pharmacology of antenatal steroids. In addition, the review highlights some potential mediators of steroid response and current research strategies aimed at possible optimization of this therapy.