New Issue | Drug Metabolism Letters

 

Drug Metabolism Letters publishes letters, original research articles, mini-reviews, thematic issues based on mini-reviews and letters, commentaries, technical notes and drug clinical trial studies on major advances in all areas of drug metabolism and disposition.

In vitro systems including CYP-450; enzyme induction and inhibition; drug-drug interactions and enzyme kinetics; pharmacokinetics, toxicokinetics, species scaling and extrapolations; P-glycoprotein and transport carriers; target organ toxicity and interindividual variability; drug metabolism and disposition studies; extrahepatic metabolism; phase I and phase II metabolism; bioactivation; recent developments for the identification of drug metabolites, reactive intermediate and glutathione conjugates.

 

dml

 

Articles from the journal: Drug Metabolism Letters Volume: 13 Issue: 1:

 

For details on the articles, please visit this link: http://www.eurekaselect.com/node/649/drug-metabolism-letters/issue/13/2601/1/9074

Editor’s Choice Article | Unequal Absorption of Radiolabeled and Nonradiolabeled Drug from the Oral Dose Leads to Incorrect Estimates of Drug Absorption and Circulating Metabolites in a Mass Balance Study

Journal Name: Drug Metabolism Letters

Author(s): Ryan H. Takahashi*, Jae H. Chang, Jodie Pang, Xiaorong Liang, Shuguang Ma.

 

plasma

 

Mass balance studies conducted using radiolabeled material (14C or 3H) definitively characterize the Absorption, Metabolism, and Excretion (AME) of a drug. A critical aspect of these studies is that the radiotracer maintains its proportion to total drug from its administration to its complete elimination from the body. In the study of GDC-0276 in beagle dogs, we observed that the 14C radiotracer proportion (specific activity) varied through the study.

High resolution-accurate mass spectrometric measurements of 12C and 14C isotopes of GDC- 0276 and its metabolites in plasma and excreta samples were used to determine the apparent specific activities, which were higher than the specific activity of the dosing formulation. Drug concentrations were adjusted to the observed specific activities to correct the readouts for GDC-0276 AME and PK. Read out full article at:  http://www.eurekaselect.com/167902/article

 

WISHING A VERY HAPPY BIRTHDAY DR. ZHIYANG ZHAO!

Dr. ZHIYANG ZHAO

DR. ZHIYANG ZHAO

EDITOR-IN-CHIEF: Drug Metabolism Letters

Alliance Pharma
Malvern, PA
USA

PRESS RELEASE – Cytochrome P450 3A4 induction

This article by Dr. Elena K. Schneider is published in Drug Metabolism Letters, Volume 12, 2018

Cystic fibrosis (CF) is the most common, genetically acquired, life-shortening chronic illness affecting young Australians today. There is no cure, and patients with CF undergo life-long and extremely costly medical treatments. Orkambi (Vertex Pharmaceuticals), the novel lumacaftor-ivacaftor combination is the first CF therapeutic that treats the CF disease itself. Worryingly, a number of conflicting reports have emerged that overshadow the clinical efficacy of this important first-in class drug. As there are no other therapeutic alternative we must optimize its use to increase efficacy while minimizing side-effects.

‘Since releases of ivacaftor-lumacaftor combination several red-flags have been raised that highlight the clinical efficacy of this combination strategy maybe be limited due to antagonistic drug-drug interactions. Our lab is invested in shedding light on the pharmacology of cystic fibrosis transmembrane conductions regulator (CFTR) drugs and we have investigated potential cytochrome interactions of ivacaftor, its major metabolites lumacaftor and tezacaftor’ says Dr Elena K Schneider, a Research Fellow from the University of Melbourne, Department of Pharmacology & Therapeutics.

In the last couple of years, Dr Schneider and her lab group have intensively worked on the pharmacology of two new breakthrough CF medications, ivacaftor and lumacaftor and is now able to provide a pharmacological and analytical platform for clinicians to improve patients’ outcomes by optimization of therapy. For example, Dr Schneider found that lumacaftor and ivacaftor-M6 metabolite markedly induced the activity of cytochrome CYP3A4; however, not ivacaftor-M1 and the novel CFTR modulator tezacaftor. She hypothesized that the cytochrome P450 3A4 induction (lumacaftor versus ivacaftor) potentially results in significantly reduced plasma concentration of ivacaftor in patients receiving Orkambi therapy which could explain the reduced efficacy. In addition to the above, Dr Schneider is looking at ADME parameters of CFTR modulators including pharmacokinetic/pharmacodynamic parameters.

Dr Elena Schneider, research fellow at University of Melbourne, is working to fill this gap in knowledge. She aims to optimise the current treatment options and improving the lives of CF patients.

For more information about the research study, please visit: http://www.eurekaselect.com/160801

 

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BENTHAM PRESS RELEASE!

BENTHAM SCIENCE PARTNERS WITH ISSX

The International Society for the Study of Xenobiotics (ISSX) signs agreement with Bentham Science Publishers to promote the journals, Current Drug Metabolism and Drug Metabolism Letters, among its members. ISSX is the premier scientific organization for researchers interested in the metabolism and disposition of xenobiotics.

Current Drug Metabolism aims to cover all the latest and outstanding developments in drug metabolism, pharmacokinetics, and drug disposition. The journal serves as an international forum for the publication of timely review articles and guest edited issues in drug metabolism. The journal covers the following general topic areas: pharmaceutics, pharmacokinetics, toxicology, and most importantly drug metabolism.

Drug Metabolism Letters publishes letters, original research articles, mini-reviews, thematic issues based on mini-reviews and letters, commentaries, technical notes and drug clinical trial studies on major advances in all areas of drug metabolism and disposition.

MOST ACCESSED ARTICLE – Mixed Matrix Method Provides A Reliable Metabolite Exposure Comparison for Assessment of Metabolites in Safety Testing (MIST) – Drug Metabolism Letters

Journal: Drug Metabolism Letters

Author(s): Ryan H. Takahashi, Cyrus Khojasteh, Matthew Wright, Cornelis E.C.A. Hop, Shuguang Ma

Graphical Abstract:

 

Abstract:

Background: The regulatory guidances on metabolites in safety testing (MIST) by US Food and Drug Administration (FDA) and International Conference on Harmonisation (ICH) describe the necessity to assess exposures of major circulating metabolites in humans at steady state relative to exposures achieved in nonclinical safety studies prior to the initiation of large scale clinical trials. This comparison can be accomplished by measuring metabolite concentrations in animals and humans with validated bioanalytical methods. However, bioanalysis of metabolites in multiple species and multiple studies is resource intensive and may impact the timelines of clinical studies.

Method: A simple, reliable and accurate method has been developed for quantitative assessment of metabolite coverage in preclinical safety species by mixing equal volume of human plasma with blank plasma of animal species and vice versa followed by an analysis using LC-SRM or LC-HRMS. Here, we explored the reliability and accuracy of this method in several development projects at Genentech and compared the results to those obtained from validated bioanalytical methods.

Results: The mixed-matrix method provided comparable accuracy (within ±20%) to those obtained from validated bioanalysis but does not require authentic standards or radiolabeled compounds, which could translate to time and resource savings in drug development.

Conclusion: Quantitative assessment of metabolite coverage in safety species can be made using mixed matrix method with similar accuracy and scientific rigor to those obtained from validated bioanalytical methods. Moving forward, we are encouraging the industry and regulators to consider accepting the mixed matrix method for assessing metabolite exposure comparisons between humans and animal species used in toxicology studies.

To access the article, please visit: http://www.eurekaselect.com/154106

 

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Highlighted Article – Mixed Matrix Method Provides A Reliable Metabolite Exposure Comparison For Assessment Of Metabolite-in-Safety Testing (MIST) – Drug Metabolism Letters

DML-Articles_10-4-Cyrus Khojasteh

To access this article, please visit: http://www.eurekaselect.com/154106/article

Upcoming Thematic Issue – Medical Imaging Technologies for IoT based Wireless Patient Monitoring

CML-THEMATIC FLYER -Dr.S.Smys

http://benthamscience.com/journals/drug-metabolism-letters/

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