GENETIC CONTROL OF DRUG LEVELS AND OF THE INDUCTION OF DRUG-METABOLIZING ENZYMES IN MAN: INDIVIDUAL VARIABILITY IN THE EXTENT OF ALLOPURINOL AND NORTRIPTYLINE INHIBITION OF DRUG METABOLISM

1971 ◽  
Vol 179 (1 Drug Metaboli) ◽  
pp. 752-772 ◽  
Author(s):  
Elliot S. Vesell ◽  
G. Thomas Passananti ◽  
Frank E. Greene ◽  
John G. Page
Keyword(s):  
Drug Metabolism ◽  
Genetic Control ◽  
Individual Variability ◽  
Drug Metabolizing Enzymes ◽  
Metabolizing Enzymes ◽  
Drug Levels

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 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 .

scholarly journals How Can Drug Metabolism and Transporter Genetics Inform Psychotropic Prescribing?

2020 ◽  
Vol 11 ◽  
Author(s):  
Beatriz Carvalho Henriques ◽  
Esther H. Yang ◽  
Diego Lapetina ◽  
Michael S. Carr ◽  
Vasyl Yavorskyy ◽  
...  
Keyword(s):  
Drug Metabolism ◽  
Drug Interactions ◽  
Psychiatric Disorders ◽  
Genetic Variants ◽  
Clinical Utility ◽  
Future Research ◽  
Drug Metabolizing Enzymes ◽  
Research Focus ◽  
Metabolizing Enzymes ◽  
Clinical Associations

Many genetic variants in drug metabolizing enzymes and transporters have been shown to be relevant for treating psychiatric disorders. Associations are strong enough to feature on drug labels and for prescribing guidelines based on such data. A range of commercial tests are available; however, there is variability in included genetic variants, methodology, and interpretation. We herein provide relevant background for understanding clinical associations with specific variants, other factors that are relevant to consider when interpreting such data (such as age, gender, drug–drug interactions), and summarize the data relevant to clinical utility of pharmacogenetic testing in psychiatry and the available prescribing guidelines. We also highlight areas for future research focus in this field.

scholarly journals Variability in human drug metabolizing cytochrome P450 CYP2C9, CYP2C19 and CYP3A5 activities caused by genetic variations in cytochrome P450 oxidoreductase

2019 ◽  
Author(s):  
Maria Natalia Rojas Velazquez ◽  
Shaheena Parween ◽  
Sameer S Udhane ◽  
Amit V Pandey
Keyword(s):  
Cytochrome P450 ◽  
Drug Metabolism ◽  
Recombinant Proteins ◽  
Correct Diagnosis ◽  
Detailed Knowledge ◽  
Drug Metabolizing Enzymes ◽  
Metabolizing Enzymes ◽  
P450 Oxidoreductase ◽  
Cytochrome P450 Oxidoreductase

AbstractA broad spectrum of human diseases are caused by mutations in the NADPH cytochrome P450 oxidoreductase (POR). Cytochrome P450 proteins perform several reactions, including the metabolism of steroids, drugs, and other xenobiotics. In 2004 the first human patients with defects in POR were reported, and over 250 variations in POR are known. Information about the effects of POR variants on drug metabolizing enzymes is limited and has not received much attention. By analyzing the POR sequences from genomics databases, we identified potentially disease-causing variations and characterized these by in vitro functional studies using recombinant proteins. Proteins were expressed in bacteria and purified for activity assays. Activities of cytochrome P450 enzymes were tested in vitro using liposomes prepared with lipids into which P450 and P450 reductase proteins were embedded. Here we are reporting the effect of POR variants on drug metabolizing enzymes CYP2C9, CYP2C19, and CYP3A5 which are responsible for the metabolism of many drugs. POR Variants A115V, T142A, A281T, P284L, A287P, and Y607C inhibited activities of all P450 proteins tested. Interestingly, the POR variant Q153R showed a reduction of 20-50% activities with CYP2C9 and CYP2C19 but had a 400% increased activity with CYP3A5. The A287P is most common POR mutation found in patients of European origin, and significantly inhibited drug metabolism activities which has important consequences for monitoring and treatment of patients. In vitro, functional assays using recombinant proteins provide a useful model for establishing the metabolic effect of genetic mutations. Our results indicate that detailed knowledge about POR variants is necessary for correct diagnosis and treatment options for persons with POR deficiency and the role of changes in drug metabolism and toxicology due to variations in POR needs to be addressed.

The activity of drug-metabolizing enzymes and the biotransformation of selected anthelmintics in the model tapeworm Hymenolepis diminuta

Parasitology ◽  
2012 ◽  
Vol 139 (6) ◽  
pp. 809-818 ◽  
Author(s):  
HANA BÁRTÍKOVÁ ◽  
IVAN VOKŘÁL ◽  
LENKA SKÁLOVÁ ◽  
VLADIMÍR KUBÍČEK ◽  
JANA FIRBASOVÁ ◽  
...  
Keyword(s):  
Drug Metabolism ◽  
Ex Vivo ◽  
Mass Spectrometric ◽  
Hymenolepis Diminuta ◽  
Drug Metabolizing Enzymes ◽  
Glutathione S Transferase ◽  
Methyl Derivative ◽  
Metabolizing Enzymes ◽  
Oxidative Metabolites

SUMMARYThe drug-metabolizing enzymes of some helminths can deactivate anthelmintics and therefore partially protect helminths against these drugs' toxic effect. The aim of our study was to assess the activity of the main drug-metabolizing enzymes and evaluate the metabolism of selected anthelmintics (albendazole, flubendazole, mebendazole) in the rat tapeworm Hymenolepis diminuta, a species often used as a model tapeworm. In vitro and ex vivo experiments were performed. Metabolites of the anthelmintics were detected and identified by HPLC with spectrofluorometric or mass–spectrometric detection. The enzymes of H. diminuta are able to reduce the carbonyl group of flubendazole, mebendazole and several other xenobiotics. Although the activity of a number of oxidation enzymes was determined, no oxidative metabolites of albendazole were detected. Regarding conjugation enzymes, a high activity of glutathione S-transferase was observed. A methyl derivative of reduced flubendazole was the only conjugation metabolite identified in ex vivo incubations of H. diminuta with anthelmintics. The results revealed that H. diminuta metabolized flubendazole and mebendazole, but not albendazole. The biotransformation pathways found in H. diminuta differ from those described in Moniezia expanza and suggest the interspecies differences in drug metabolism not only among classes of helminths, but even among tapeworms.

scholarly journals Pharmacogenetics of Carbamazepine and Valproate: Focus on Polymorphisms of Drug Metabolizing Enzymes and Transporters

2021 ◽  
Vol 14 (3) ◽  
pp. 204
Author(s):  
Teresa Iannaccone ◽  
Carmine Sellitto ◽  
Valentina Manzo ◽  
Francesca Colucci ◽  
Valentina Giudice ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Drug Response ◽  
Current Knowledge ◽  
Individual Variability ◽  
Mood Stabilizers ◽  
Drug Metabolizing Enzymes ◽  
Efficacy And Safety ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Metabolizing Enzymes ◽  
Drug Pharmacokinetics

Pharmacogenomics can identify polymorphisms in genes involved in drug pharmacokinetics and pharmacodynamics determining differences in efficacy and safety and causing inter-individual variability in drug response. Therefore, pharmacogenomics can help clinicians in optimizing therapy based on patient’s genotype, also in psychiatric and neurological settings. However, pharmacogenetic screenings for psychotropic drugs are not routinely employed in diagnosis and monitoring of patients treated with mood stabilizers, such as carbamazepine and valproate, because their benefit in clinical practice is still controversial. In this review, we summarize the current knowledge on pharmacogenetic biomarkers of these anticonvulsant drugs.

Sign in / Sign up

Export Citation Format

Share Document