Clinical reappraisal of the influence of drug-transporter polymorphisms in epilepsy.

Expert Opin Drug Metab Toxicol. 2018 May;14(5):505-512

Authors: Orlandi A, Paolino MC, Striano P, Parisi P

Abstract
INTRODUCTION: Although novel antiepileptic drugs (AEDs) have been recently released, the issue of drug resistance in epileptic patients remains unsolved and largely unpredictable. Areas covered: We aim to assess the clinical impact of genetic variations that may influence the efficacy of medical treatment in epilepsy patients. Indeed, many genes, including genes encoding drug transporters (ABCB1), drug targets (SCN1A), drug-metabolizing enzymes (CYP2C9, CYP2C19), and human leucocyte antigen (HLA) proteins, may regulate the mechanisms of drug resistance in epilepsy. This review specifically focuses on the ABC genes, which encode multidrug resistance-associated proteins (MRPs) and may reduce the blood-brain barrier penetration of anticonvulsant AEDs. Expert opinion: Drug resistance remains a crucial problem in epilepsy patients. Pharmacogenomic studies may improve our understanding of drug responses and drug resistance by exploring the impact of gene variants and predicting drug responses and tolerability.

PMID: 29804481 [PubMed - indexed for MEDLINE]

Simultaneous Discrimination of Single-Base Mismatch and Full Match Using a Label-Free Single-Molecule Strategy.

Anal Chem. 2018 Jun 06;:

Authors: Yang Q, Ai T, Lv Y, Huang Y, Geng J, Xiao D, Zhou C

Abstract
Identification of single-base mismatches has found wide applications in disease diagnosis, pharmacogenetics and population genetics. However, there is still a great challenge in the simultaneous discrimination of single-base mismatch and full match. Combined with a nanopore electrochemical sensor, a shared-stem structure of molecular beacon (MB) was designed that did not need the labeling, but achieved an enhanced signal-to-background ratio (SBR) of ~10E4, high thermodynamic stability to bind with target sequences and a fast hybridization rate. Fully matched and single-base mismatched sequences were simultaneously discriminated at the single-molecule level, which is expected to have potential applications ranging from the quick detection, early clinical diagnostics to point-of-care research.

PMID: 29874049 [PubMed - as supplied by publisher]

Identification of a Genomic Region Between SLC29A1 and HSP90AB1 Associated with Risk of Bevacizumab-Induced Hypertension: CALGB 80405 (Alliance).

Clin Cancer Res. 2018 Jun 05;:

Authors: Li M, Mulkey F, Jiang C, O'Neill BH, Schneider BP, Shen F, Friedman PN, Momozawa Y, Kubo M, Niedzwiecki D, Hochster HS, Lenz HJ, Atkins JN, Rugo HS, Halabi S, Kelly WK, McLeod HL, Innocenti F, Ratain MJ, Venook A, Owzar K, Kroetz D

Abstract
PURPOSE: Bevacizumab is a VEGF-specific angiogenesis inhibitor indicated as an adjunct to chemotherapy for the treatment of multiple cancers. Hypertension is commonly observed during bevacizumab treatment, and high-grade toxicity can limit therapy or lead to cardiovascular complications. The factors that contribute to interindividual variability in blood pressure rise during bevacizumab treatment are not well understood.
EXPERIMENTAL DESIGN: To identify genomic regions associated with bevacizumab-induced hypertension risk, sequencing of candidate genes and flanking regulatory regions was performed on 61 bevacizumab-treated patients (19 cases developed early-onset grade 3 hypertension and 42 controls had no reported hypertension in the first six cycles of treatment). SNP-based tests for common variant associations and gene-based tests for rare variant associations were performed in 174 candidate genes.
RESULTS: Four common variants in independent linkage disequilibrium blocks between SLC29A1 and HSP90AB1 were among the top associations. Validation in larger bevacizumab-treated cohorts supported association between rs9381299 with early grade 3+ hypertension (P = 0.01, OR 2.4) and systolic blood pressure > 180 mmHg (P = 0.02, OR 2.1). rs834576 was associated with early grade 3+ hypertension in CALGB 40502 (P = 0.03, OR 2.9). These SNP regions are enriched for regulatory elements that may potentially increase gene expression. In vitro overexpression of SLC29A1 in human endothelial cells disrupted adenosine signaling and reduced nitric oxide levels that were further lowered upon bevacizumab exposure.
CONCLUSIONS: The genomic region between SLC29A1 and HSP90AB1 and its role in regulating adenosine signaling are key targets for further investigation into the pathogenesis of bevacizumab-induced hypertension.

PMID: 29871907 [PubMed - as supplied by publisher]

Expression profiling and functional annotation of noncoding genes across 11 distinct organs in rat development.

Sci Rep. 2016 12 09;6:38575

Authors: Wen Z, Chen G, Zhu S, Zhu J, Li B, Song Y, Li S, Shi L, Zheng Y, Li M

Abstract
Accumulating evidence suggests that noncoding RNAs (ncRNAs) have important regulatory functions. However, lacking of functional annotations for ncRNAs hampered us from carrying out the subsequent functional or predictive research. Here we dissected the expression profiles of 3,458 rat noncoding genes using rat bodymap RNA-sequencing data consisting of 11 solid organs over four developmental stages (juvenile, adolescent, adult and aged) from both sexes, and conducted a comprehensive analysis of differentially expressed noncoding genes (DEnGs) between various conditions. We then constructed a co-expression network between protein-coding and noncoding genes to infer biological functions of noncoding genes. Modules of interest were linked to online databases including DAVID for functional annotation and pathway analysis. Our results indicated that noncoding genes are functionally enriched through pathways similar to those of protein-coding genes. Terms about development of the immune system were enriched with genes from age-related modules, whereas terms about sexual reproduction were enriched with genes in sex-related modules. We also built connection networks on some significant modules to visualize the interactions and regulatory relationship between protein-coding and noncoding genes. Our study could improve our understanding and facilitate a deeper investigation on organ/age/sex-related regulatory events of noncoding genes, which may lead to a superior preclinical model for drug development and translational medicine.

PMID: 27934932 [PubMed - indexed for MEDLINE]

Drug metabolism and transport gene polymorphisms and efavirenz adverse effects in Brazilian HIV-positive individuals.

J Antimicrob Chemother. 2018 Jun 03;:

Authors: de Almeida TB, de Azevedo MCVM, Pinto JFDC, Ferry FRA, da Silva GAR, de Castro IJ, Baker P, Tanuri A, Haas DW, Cardoso CC

Abstract
Objectives: There are limited data regarding efavirenz pharmacogenetics in admixed populations. The Brazilian population is highly admixed. In a Brazilian cohort, we sought to characterize associations between efavirenz adverse effects (all-cause and CNS) and polymorphisms in seven genes known or suspected to affect efavirenz metabolism and transport.
Methods: We studied 225 HIV-positive individuals who had been prescribed efavirenz-containing regimens at a hospital in Rio de Janeiro, Brazil. Eighty-nine cases had efavirenz adverse effects, including 43 with CNS adverse effects, while 136 controls had no adverse effect of any antiretroviral after treatment for at least 6 months. A total of 67 candidate polymorphisms in ABCB1, CYP2A6, CYP2B6, CYP3A4, CYP3A5, NR1I2 and NR1I3 genes were selected for association analysis. Admixture was assessed using 28 ancestry-informative polymorphisms previously validated for the Brazilian population. Associations were evaluated with logistic regression models adjusted for sex and genetic ancestry.
Results: There was extensive African, European and Native American admixture in the cohort. Increased all-cause adverse effects were associated with the CYP2B6 genotype combination 15582CC-516TT-983TT (OR = 7.26, P = 0.003) and with the CYP2B6 slow metabolizer group 516TT or 516GT-983CT (OR = 3.10, P = 0.04). CNS adverse effects were nominally associated with CYP3A4 rs4646437 (OR = 4.63, P = 0.014), but not after adjusting for multiple comparisons.
Conclusions: In a highly admixed Brazilian cohort, the CYP2B6 slow metabolizer genotype was associated with an increased risk of efavirenz adverse effects.

PMID: 29868865 [PubMed - as supplied by publisher]

Betulinic Acid Exerts Cytotoxic Activity Against Multidrug-Resistant Tumor Cells via Targeting Autocrine Motility Factor Receptor (AMFR).

Front Pharmacol. 2018;9:481

Authors: Saeed MEM, Mahmoud N, Sugimoto Y, Efferth T, Abdel-Aziz H

Abstract
Betulinic acid (BetA) is a naturally occurring pentacyclic triterpene isolated from the outer bark of white-barked birch trees and many other medicinal plants. Here, we studied betulinic acid's cytotoxic activity against drug-resistant tumor cell lines. P-glycoprotein (MDR1/ABCB1) and BCRP (ABCG2) are known ATP-binding cassette (ABC) drug transporters that mediating MDR. ABCB5 is a close relative to ABCB1, which also mediates MDR. Constitutive activation of the EGF receptor is tightly linked to the development of chemotherapeutic resistance. BetA inhibited P-gp, BCRP, ABCB5 and mutation activated EGFR overexpressing cells with similar efficacy as their drug-sensitive parental counterparts. Furthermore, the mRNA expressions of ABCB1, BCRP, ABCB5 and EGFR were not related to the 50% inhibition concentrations (IC50) for BetA in a panel of 60 cell lines of the National Cancer Institute (NCI), USA. In addition to well-established MDR mechanisms, we attempted to identify other molecular mechanisms that play a role in mediating BetA's cytotoxic activity. For this reason, we performed COMPARE and hierarchical cluster analyses of the transcriptome-wide microarray-based mRNA expression of the NCI cell lines panel. Various genes significantly correlating to BetA's activity were involved in different biological processes, e.g., cell cycle regulation, microtubule formation, signal transduction, transcriptional regulation, chromatin remodeling, cell adhesion, tumor suppression, ubiquitination and proteasome degradation. Immunoblotting and in silico analyses revealed that the inhibition of AMFR activity might be one of the mechanisms for BetA to overcome MDR phenotypes. In conclusion, BetA may have therapeutic potential for the treatment of refractory tumors.

PMID: 29867487 [PubMed]

Pharmacogenetic Aspects of the Interaction of AT1 Receptor Antagonists With ATP-Binding Cassette Transporter ABCG2.

Front Pharmacol. 2018;9:463

Authors: Ripperger A, Krischer A, Robaa D, Sippl W, Benndorf RA

Abstract
The ATP-binding cassette transporter ABCG2 (BCRP and MXR) is involved in the absorption, distribution, and elimination of numerous drugs. Thus, drugs that are able to reduce the activity of ABCG2, e.g., antihypertensive AT1 receptor antagonists (ARBs), may cause drug-drug interactions and compromise drug safety and efficacy. In addition, genetic variability within the ABCG2 gene may influence the ability of the transporter to interact with ARBs. Thus, the aim of this study was to characterize the ARB-ABCG2 interaction in the light of naturally occurring variations (F489L, R482G) or amino acid substitutions with in silico-predicted relevance for the ARB-ABCG2 interaction (Y469A; M483F; Y570A). For this purpose, ABCG2 variants were expressed in HEK293 cells and the impact of ARBs on ABCG2 activity was studied in vitro using the pheophorbide A (PhA) efflux assay. First, we demonstrated that both the F489L and the Y469A substitution, respectively, reduced ABCG2 protein levels in these cells. Moreover, both substitutions enhanced the inhibitory effect of candesartan cilexetil, irbesartan, losartan, and telmisartan on ABCG2-mediated PhA efflux, whereas the R482G substitution blunted the inhibitory effect of candesartan cilexetil and telmisartan in this regard. In contrast, the ARB-ABCG2 interaction was not altered in cells expressing either the M483F or the Y570A variant, respectively. In conclusion, our data indicate that the third transmembrane helix and adjacent regions of ABCG2 may be of major importance for the interaction of ARBs with the ABC transporter. Moreover, we conclude from our data that individuals carrying the F489L polymorphism may be at increased risk of developing ABCG2-related drug-drug interactions in multi-drug regimens involving ARBs.

PMID: 29867471 [PubMed]

The First Free Africans in America: HLA Study in San Basilio de Palenque (Colombia).

Hum Immunol. 2018 Jun 01;:

Authors: Arnaiz-Villena A, Juarez I, Palacio-Gruber J, Muñiz E, Campos C, Martinez-Laso J, Nieto J, Lopez-Nares A, Martin-Villa JM, Silvera C

Abstract
Original San Basilio de Palenque population (North Colombia) fled from Spanish traders that carried them as slaves and they funded in nearby Maria mountains a fortified town (Palenque). They started helping new Africans brought as slaves to flee and join them. Most of them spoke a Bantu-Congo language and nowadays they speak the only one extant Bantu-Spanish Creole language. Spanish Crown were forced to issue a decree declaring them free (1691 AD), more than 100 years before than Haiti Republic existed. HLA-A, -B, -DRB1 and -DQB1 alleles were studied and further computer procedures were performed with Arlequin 3.5 software. No Amerindian or Europeans gene flow to this population was found. However, three specific HLA extended haplotypes are found in this population, which may reflect an isolation from other Africans or Afro-Americans also. This may be due to the maintenance of their own African culture, and even their unique Creole language.

PMID: 29864459 [PubMed - as supplied by publisher]

Under explored epigenetic modulators: role in glioma chemotherapy.

Eur J Pharmacol. 2018 Jun 01;:

Authors: Chen YH, Zeng WJ, Wen ZP, Chen Q, Chen XP

Abstract
Patients with somatic mutations of epigenetic regulators are characterized by aberrant chromatin modification patterns. Recent mechanistic studies pairing chemical tool compounds and deep-sequencing technology have greatly broadened our understanding of epigenetic regulation in glioma progression and underpinned alternative treatment of epigenetic inhibitors. However, the effect of most inhibitors is condition-dependent, and the overall results of clinical trials still have not been applied to patients. There is an intense need to develop more potent and specific compounds as well as identify the population who may achieve clinical benefits. Besides, combination therapy with conventional therapeutics is another alternative strategy. In this review, we summarize well-characterized chemical probes in glioma research and clinical translation. We also discuss the target population and combination of therapy regimens of various agents. In a holistic sense, we try to provide guidance for selecting targeted chemical probes and pave the way for personalized rational therapy.

PMID: 29864410 [PubMed - as supplied by publisher]

Opportunities and Obstacles in Genotypic Prediction of Cytochrome P450 Phenotypes.

Expert Opin Drug Metab Toxicol. 2018 Jun 04;:

Authors: McGraw J, Gerhardt A, Morris TC

PMID: 29863909 [PubMed - as supplied by publisher]

REST, not REST4, is a risk factor associated with radiotherapy plus chemotherapy efficacy in glioma.

Drug Des Devel Ther. 2018;12:1363-1371

Authors: Li C, Zou H, Wang Z, Tang X, Fan X, Zhang K, Liu J, Li Z

Abstract
Background/aim: Repressor element silencing transcription factor (REST) is a transcription repressor, expressed in several malignancies. This study aims to evaluate the prognostic values of REST and its splicing variant REST4 in glioma, and investigate the potential correlation between REST and REST4.
Methods: REST and REST4 expression values were evaluated by qRT-PCR in 89 patients with gliomas and 10 with normal brain tissues.
Results: Upregulation of REST was related to higher World Health Organization (WHO) grade, larger tumor size, higher ki67, and higher p53 positive rate. After radiotherapy+temozolomide (RT+TMZ) treatment, low REST expression patients could get better therapeutic efficacy (P=0.031). The positive rate of REST4 expression was only 13.5% in glioma tissues, and REST4 expression was not associated with clinical characteristics and REST expression in this study.
Conclusions: REST was a prognostic factor in glioma, while REST4 was not. REST expression can be a predictor in evaluating the survival outcome of gliomas patients treated with RT+TMZ after surgery.

PMID: 29861627 [PubMed - in process]

Ligand-dependent EphA7 signaling inhibits prostate tumor growth and progression.

Cell Death Dis. 2017 Oct 12;8(10):e3122

Authors: Li S, Wu Z, Ma P, Xu Y, Chen Y, Wang H, He P, Kang Z, Yin L, Zhao Y, Zhang X, Xu X, Ma X, Guan M

Abstract
The downregulation of receptor tyrosine kinase EphA7 is frequent in epithelial cancers and linked to tumor progression. However, the detailed mechanism of EphA7-mediated prostate tumor progression remains elusive. To test the role of EphA7 receptor in prostate cancer (PCa) progression directly, we generated EphA7 receptor variants that were either lacking the cytoplasmic domain or carrying a point mutation that inhibits its phosphorylation by site-directed mutagenesis. Overexpression of wild-type (WT) EphA7 in PCa cells resulted in decreased tumor volume and increased tumor apoptosis in primary tumors. In addition, ectopic expression of WT EphA7 both can delay PCa cell proliferation and could inhibit PCa cell migration and invasion. This protein can also induce PCa cell apoptosis that correlated with increasing the protein expression levels of Bax, elevating the caspase-3 activities, reducing the protein expression levels of Bcl-2 and facilitating the dephosphorylation of Akt, which is further increased by the stimulation of ephrinA5-Fc. However, expression of these EphA7 mutants in PCa cells has no effect in vivo and in vitro. The expression of EphA7 and ephrinA5 was significantly decreased in PCa specimens compared with BPH tissues or paired normal tissues. Moreover, the phosphorylation of EphA7 was positively related with ephrinA5 expression in human prostate tissues. In sum, receptor phosphorylation of EphA7, at least in part, suppress PCa tumor malignancy through targeting PI3K/Akt signaling pathways.

PMID: 29022918 [PubMed - indexed for MEDLINE]

Methylomes of renal cell lines and tumors or metastases differ significantly with impact on pharmacogenes.

Sci Rep. 2016 07 20;6:29930

Authors: Winter S, Fisel P, Büttner F, Rausch S, D'Amico D, Hennenlotter J, Kruck S, Nies AT, Stenzl A, Junker K, Scharpf M, Hofmann U, van der Kuip H, Fend F, Ott G, Agaimy A, Hartmann A, Bedke J, Schwab M, Schaeffeler E

Abstract
Current therapies for metastatic clear cell renal cell carcinoma (ccRCC) show limited efficacy. Drug efficacy, typically investigated in preclinical cell line models during drug development, is influenced by pharmacogenes involved in targeting and disposition of drugs. Here we show through genome-wide DNA methylation profiling, that methylation patterns are concordant between primary ccRCC and macro-metastases irrespective of metastatic sites (rs ≥ 0.92). However, 195,038 (41%) of all investigated CpG sites, including sites within pharmacogenes, were differentially methylated (adjusted P < 0.05) in five established RCC cell lines compared to primary tumors, resulting in altered transcriptional expression. Exemplarily, gene-specific analyses of DNA methylation, mRNA and protein expression demonstrate lack of expression of the clinically important drug transporter OCT2 (encoded by SLC22A2) in cell lines due to hypermethylation compared to tumors or metastases. Our findings provide evidence that RCC cell lines are of limited benefit for prediction of drug effects due to epigenetic alterations. Similar epigenetic landscape of ccRCC-metastases and tumors opens new avenue for future therapeutic strategies.

PMID: 27435027 [PubMed - indexed for MEDLINE]

The readability of iPledge program patient education materials.

J Am Acad Dermatol. 2018 May 31;:

Authors: Howard R, Smith G

PMID: 29860044 [PubMed - as supplied by publisher]

Drug-induced hyperglycaemia and diabetes: pharmacogenomics perspectives.

Arch Pharm Res. 2018 Jun 01;:

Authors: Liu MZ, He HY, Luo JQ, He FZ, Chen ZR, Liu YP, Xiang DX, Zhou HH, Zhang W

Abstract
Drug-induced diabetes is widely reported in clinical conditions, and it is becoming a global issue because of its potential to increase the risk of severe cardiovascular complications. However, which drug mechanisms exert their diabetogenic effects and why the effects present significant inter-individual differences remain largely unknown. Pharmacogenomics, which is the study of how genomic variation influences drug responses, provides an explanation for individual differences in drug-induced diabetes. We highlight that pharmacogenomics can be involved in regulating the expression of genes in signaling pathways related to the pharmacokinetics or pharmacodynamics of drugs or the pathogenesis of diabetes, contributing to the differences in drug-induced glucose impairment. The pharmacogenomics studies of the major diabetogenic drugs are reviewed, including calcineurin inhibitors, antipsychotics, hormones, and antihypertensive drugs. We intend to elucidate the genetic basis of drug-induced diabetes and pave the way for the precise use of these drugs in the clinic.

PMID: 29858981 [PubMed - as supplied by publisher]

The development of probiotics therapy to obesity: a therapy that has gained considerable momentum.

Hormones (Athens). 2018 Apr 16;:

Authors: Kang Y, Cai Y

Abstract
Obesity is a growing epidemic worldwide. The most frequent cause leading to the development of obesity is an imbalance between energy intake and energy expenditure. The gut microbiota is an environmental factor involved in obesity and metabolic disorders which reveals that obese animal and human subjects present alterations in the composition of the gut microbiota compared to their lean counterparts. Furthermore, evidence has so far demonstrated that the gut microbiota, which influences whole-body metabolism, by affecting energy balance, but also inflammation and gut barrier function, integrates peripheral and central food intake regulatory signals, thereby altering body weight. At the same time, these data suggest that species of intestinal commensal bacteria may play either a pathogenic or a protective role in the development of obesity. Though still a relatively nascent field of research, evidence to date suggests that manipulating the gut microbiome may represent effective treatment for the prevention or management of obesity. Various studies have described the beneficial effects of specific bacteria on the characteristics of obesity. However, the available data in this field remain limited and the relevant scientific work has only recently begun. This review aims to summarize the notable advances and contributions in the field that may prove useful for identifying probiotics that target obesity and its related disorders.

PMID: 29858841 [PubMed - as supplied by publisher]

Allele Frequency Net Database.

Methods Mol Biol. 2018;1802:49-62

Authors: Gonzalez-Galarza FF, McCabe A, Melo Dos Santos EJ, Takeshita L, Ghattaoraya G, Jones AR, Middleton D

Abstract
The allele frequency net database (AFND, http://www.allelefrequencies.net ) is an online web-based repository that contains information on the frequencies of immune-related genes and their corresponding alleles in worldwide human populations. At present, the system contains data from 1505 populations in more than ten million individuals on the frequency of genes from different polymorphic regions including data for the human leukocyte antigens (HLA) system. This resource has been widely used in a variety of contexts such as histocompatibility, immunology, epidemiology, pharmacogenetics, and population genetics, among many others. In this chapter, we present some of the more commonly used searching mechanisms and some of the most recent developments included in AFND.

PMID: 29858801 [PubMed - in process]

Pharmacogenetic testing in the Veterans Health Administration (VHA): policy recommendations from the VHA Clinical Pharmacogenetics Subcommittee.

Genet Med. 2018 Jun 01;:

Authors: Vassy JL, Stone A, Callaghan JT, Mendes M, Meyer LJ, Pratt VM, Przygodzki RM, Scheuner MT, Wang-Rodriguez J, Schichman SA, VHA Clinical Pharmacogenetics Subcommittee

Abstract
PURPOSE: The Veterans Health Administration (VHA) Clinical Pharmacogenetics Subcommittee is charged with making recommendations about whether specific pharmacogenetic tests should be used in healthcare at VHA facilities. We describe a process to inform VHA pharmacogenetic testing policy.
METHODS: After developing consensus definitions of clinical validity and utility, the Subcommittee identified salient drug-gene pairs with potential clinical application in VHA. Members met monthly to discuss each drug-gene pair, the evidence of clinical utility for the associated pharmacogenetic test, and any VHA-specific testing considerations. The Subcommittee classified each test as strongly recommended, recommended, or not routinely recommended before drug initiation.
RESULTS: Of 30 drug-gene pair tests reviewed, the Subcommittee classified 4 (13%) as strongly recommended, including HLA-B*15:02 for carbamazepine-associated Stevens-Johnston syndrome and G6PD for rasburicase-associated hemolytic anemia; 12 (40%) as recommended, including CYP2D6 for codeine toxicity; and 14 (47%) as not routinely recommended, such as CYP2C19 for clopidogrel dosing.
CONCLUSION: Only half of drug-gene pairs with high clinical validity received Subcommittee support for policy promoting their widespread use across VHA. The Subcommittee generally found insufficient evidence of clinical utility or available, effective alternative strategies for the remainders. Continual evidence review and rigorous outcomes research will help promote the translation of pharmacogenetic discovery to healthcare.

PMID: 29858578 [PubMed - as supplied by publisher]

Cytochrome P450 genotype-guided drug therapies: an update on current states.

Clin Exp Pharmacol Physiol. 2018 Jun 02;:

Authors: Dong AN, Tan BH, Pan Y, Ong CE

Abstract
Over the past two decades, knowledge of the role and clinical value of pharmacogenetic markers has expanded so that individualized pre-emptive therapy based on genetic background of patients could be within reach for clinical implementation. This is evidenced from the frequent updating of drug labels that incorporates pharmacogenetic information (where compelling data become available) by the regulatory agencies (such as FDA), and the periodical publication of guidelines of specific therapeutic recommendations based on the results of pharmacogenetic tests by the pharmacogenetics working groups or consortiums of professional bodies. Clinical relevance of the cytochrome P450 (CYP) polymorphism related to dose, effectiveness and/or toxicity of key drugs are presented in this review, including that of warfarin, clopidogrel, tricyclic antidepressants, and proton pump inhibitors. Prospect for routine clinical application of CYP genotyping before prescribing drugs is still currently unclear due to challenges and barriers associated with availability of well-defined and validated pharmacogenetic studies, the interpretation, result reporting and potential error of genotype testing, involvement of non-genetic factors, and other patient's demographic and disease conditions. Further studies to provide additional supporting clinical data and acceleration of pharmacogenetic testing standards and techniques should help improve the evidence base needed for clinical utility and hence move the implementation of genotype-guided therapy in clinical practice a step closer to reality. This article is protected by copyright. All rights reserved.

PMID: 29858511 [PubMed - as supplied by publisher]

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