Pharmacogenomics: Translating Functional Genomics into Rational Therapeutics

Science ◽  
1999 ◽  
Vol 286 (5439) ◽  
pp. 487-491 ◽  
Author(s):  
William E. Evans ◽  
Mary V. Relling
Keyword(s):  
Drug Therapy ◽  
Drug Discovery ◽  
Drug Targets ◽  
Drug Disposition ◽  
Scientific Basis ◽  
Genetic Constitution ◽  
Drug Metabolizing Enzymes ◽  
Metabolizing Enzymes ◽  
Interindividual Differences ◽  
Pharmacogenomic Studies

Genetic polymorphisms in drug-metabolizing enzymes, transporters, receptors, and other drug targets have been linked to interindividual differences in the efficacy and toxicity of many medications. Pharmacogenomic studies are rapidly elucidating the inherited nature of these differences in drug disposition and effects, thereby enhancing drug discovery and providing a stronger scientific basis for optimizing drug therapy on the basis of each patient's genetic constitution.

scholarly journals Tailoring Drug Therapy Based on Genotype

2012 ◽  
Vol 25 (4) ◽  
pp. 413-416 ◽  
Author(s):  
Larisa H. Cavallari
Keyword(s):  
Human Immunodeficiency Virus ◽  
Drug Therapy ◽  
Coronary Artery ◽  
Genetic Information ◽  
Drug Targets ◽  
Drug Disposition ◽  
Warfarin Dose ◽  
Drug Metabolizing Enzymes ◽  
Metabolizing Enzymes ◽  
Immunodeficiency Virus

Polymorphisms in genes encoding drug metabolizing enzymes, drug transporters, and drug targets can influence drug effects and contribute to inter-individual differences in drug response. Genotype for drug metabolizing enzymes and drug transporters can influence drug disposition in the body (pharmacokinetics), whereas genotype for drug targets may influence sensitivity to a drug (pharmacodynamics). In some cases, response to a particular drug is contingent on genotype for both drug disposition and drug target proteins. For example, warfarin dose requirements are influenced by both cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex 1 (VKORC1) genotypes. The goal of pharmacogenetics is to maximize drug effectiveness while limiting drug toxicity, based on an individual's DNA. Over 80 drugs now contain genetic information in their FDA-approved labeling. In addition to influencing warfarin dose requirements, genotype contributes to the efficacy of clopidogrel in coronary artery disease, risk for hypersensitivity reactions to abacavir in the treatment of human immunodeficiency virus, risk for statin-induced myopathy, and responses to numerous other drugs. Genetic information is routinely integrated into decisions regarding cancer chemotherapy and treatment for human immunodeficiency virus. Clinical implementation of pharmacogenetics is becoming a reality in other therapeutic areas, such as for patients requiring dual antiplatelet therapy following coronary artery stent implantation. In the future, it is possible that individuals will be broadly genotyped so that genetic information can guide drug therapy decisions throughout their lifetime.

scholarly journals Pharmacogenetics of Antiplatelet Drugs

2002 ◽  
Vol 2 ◽  
pp. 791-800 ◽  
Author(s):  
Ronan Curtin ◽  
Desmond J. Fitzgerald
Keyword(s):  
Clinical Trials ◽  
Drug Targets ◽  
Genetic Factors ◽  
Adverse Outcome ◽  
Antiplatelet Agents ◽  
Genetic Variations ◽  
Antiplatelet Drugs ◽  
Drug Metabolizing Enzymes ◽  
Gene Variant ◽  
Metabolizing Enzymes

Pharmacogenetics refers to the genetic factors that influence the response to a drug, often involving genetic variations in drug metabolizing enzymes. The pharmacogenetics of antiplatelet agents is in its infancy and largely reflects variations in drug targets or related genes. One particular gene variant, the PlA2polymorphism of the glycoprotein (GP) IIb/IIIa receptor, is now emerging as a probable determinant of the response to antiplatelet agents including GPIIb/IIIa antagonists. This variant may in part explain the heterogeneity in the response to GPIIb/IIIa antagonists. The PlA2genotype appears to be associated with an adverse outcome in patients treated with an oral GPIIb/IIIa antagonist and may be a factor in the observed failure of these agents in unselected populations. However, there are preliminary indications that other antiplatelet agents may have an enhanced effect in PlA2subjects. Further clinical trials in particular are required to definitively characterize the pharmacogenetic effect of PlA2. Other polymorphisms are also likely to contribute to the pharmacogenetics of antiplatelet agents, but these await investigation.

A pharmacogenetic study of docetaxel and thalidomide in patients with androgen-independent prostate cancer (AIPC) using targeted human DMET genotyping platform

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3580-3580
Author(s):  
J. F. Deeken ◽  
T. Cormier ◽  
D. K. Price ◽  
S. Steinberg ◽  
K. Tran ◽  
...  
Keyword(s):  
Clinical Response ◽  
Phase Ii ◽  
Drug Disposition ◽  
Individual Variability ◽  
Response To Therapy ◽  
Drug Metabolizing Enzymes ◽  
Nucleotide Polymorphisms ◽  
Pharmacogenetic Study ◽  
Metabolizing Enzymes ◽  
Genotyping Platform

3580 Background: Pharmacogenetic research holds the promise of individualizing cancer therapy by reducing inter-individual variability in drug response, thus enhancing efficacy and reducing toxicity. Past research has been limited due to the lack of a robust genotyping platform that can screen for single nucleotide polymorphisms (SNPs) in the dozens of genes known to be involved in drug disposition. We pilot tested the new Affymetrix Targeted Human Drug Metabolizing Enzymes and Transporter (DMET) 1.0 panel in an exploratory study of docetaxel and thalidomide. The DMET 1.0 panel tests for 1,229 genetic variations in 169 drug disposition genes, including 49 CYP450 genes, 73 non-CYP genes, and 47 transporters. Methods: DNA samples from 47 patients with AIPC enrolled in a randomized phase II trial using docetaxel and thalidomide vs. docetaxel alone were genotyped using the DMET 1.0 panel. Patients’ response was determined using RECIST criteria. Toxicities were graded using the NCI-CTC, and patients were identified if they experienced grade 3 or 4 toxicity. Given the distinct side effect profiles of these two drugs, specific toxicities were assigned as being due to either docetaxel or thalidomide. An association between the SNP parameters and clinical response or toxicity was tested using Mehta’s modification to Fisher’s exact test. Reported results were limited to those where p<0.01. Results: Six SNPs in three genes were associated with response to therapy: PPAR-delta (p=0.0011), SULT1C2 (p=0.0083), and CHST3 (4 SNPs, p=0.0001 to 0.0034). For toxicities associated with docetaxel, five SNPs in three genes were identified: UGT1A1 (2 SNPs, p=0.0009 to 0.0094), UGT1A9 (2 SNPs, p=0.0016 to 0.0096), and CYP2A7 (p=0.0027). SNPs in CYP2B6 (p=0.0033), ABCC1 (p=0.0036), and ABCC6 (p=0.0075) were associated with toxicities from thalidomide. Conclusion: We identified nine genes in which SNPs were potentially significantly associated with clinical response and toxicity to treatment. These results highlight the important role that non-CYP450 and phase II drug metabolizing enzymes may play in the efficacy and disposition of docetaxel and thalidomide. Confirmatory studies are warranted. No significant financial relationships to disclose.

scholarly journals Application of a novel regulatable Cre recombinase system to define the role of liver and gut metabolism in drug oral bioavailability

2015 ◽  
Vol 465 (3) ◽  
pp. 479-488 ◽  
Author(s):  
Colin J. Henderson ◽  
Lesley A. McLaughlin ◽  
Maria Osuna-Cabello ◽  
Malcolm Taylor ◽  
Ian Gilbert ◽  
...  
Keyword(s):  
Mouse Model ◽  
Oral Bioavailability ◽  
Drug Disposition ◽  
Single Agent ◽  
Cre Recombinase ◽  
Drug Metabolizing Enzymes ◽  
Relative Role ◽  
Metabolizing Enzymes ◽  
Gut Metabolism

We describe a mouse model where the functions of key drug-metabolizing enzymes are deleted in liver or liver and gut by application of a single agent, allowing the relative role of each tissue in drug disposition to be established.

scholarly journals Pharmacogenetics of drug-metabolizing enzymes: implications for a safer and more effective drug therapy

2005 ◽  
Vol 360 (1460) ◽  
pp. 1563-1570 ◽  
Author(s):  
Magnus Ingelman-Sundberg ◽  
Cristina Rodriguez-Antona
Keyword(s):  
Gene Expression ◽  
Cytochrome P450 ◽  
Drug Therapy ◽  
Adverse Effects ◽  
Drug Metabolism ◽  
Drug Metabolizing Enzymes ◽  
Drug Reactions ◽  
Metabolizing Enzymes ◽  
Drug Treatments ◽  
Polymorphic Enzymes

The majority of phase I- and phase II-dependent drug metabolism is carried out by polymorphic enzymes which can cause abolished, quantitatively or qualitatively decreased or enhanced drug metabolism. Several examples exist where subjects carrying certain alleles do not benefit from drug therapy due to ultrarapid metabolism caused by multiple genes or by induction of gene expression or, alternatively, suffer from adverse effects of the drug treatment due to the presence of defective alleles. It is likely that future predictive genotyping for such enzymes might benefit 15–25% of drug treatments, and thereby allow prevention of adverse drug reactions and causalities, and thus improve the health of a significant fraction of the patients. However, it will take time before this will be a reality within the clinic. We describe some important aspects in the field with emphasis on cytochrome P450 and discuss also polymorphic aspects of foetal expression of CYP3A5 and CYP3A7 .

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