Track topics on Twitter Track topics that are important to you
Recent regulatory guidance suggests that metabolites identified in human plasma should be present at equal or greater levels in one of the animal species used in safety assessments. In this report, an HPLC-MS/MS method is described whereby quantitative comparisons of exposures to metabolites between species can be obtained in the absence of authentic standards of the metabolites, calibration curves, and other attributes of standard bioanalytical methods. This novel method was tested using six drug/metabolites combinations. Plasma samples from animal are mixed with control plasma from human, and vice-versa, to remove possible differential effects of matrices. Through multiple ion monitoring triggered enhanced product ion (EPI) scans, all metabolites were qualitatively confirmed and daughter ions were selected for the most sensitive mass transitions to trigger EPI scans. Direct comparisons of metabolites in animal vs. human plasma were achieved by calculating the peak area ratios of the metabolites vs. internal standard. Linearity of instrument responses was established by serial dilution. A statistical analysis demonstrated that experimentally measured ratios of the parent and metabolites in rat vs. human correlated well with the nominal ratios of concentrations using linear regression with an average slope of 0.99±0.08 (r: 0.994±0.005). This analysis showed that if the experimentally determined ratio of mass spectrometer responses is ≥2.0 then the actual exposure ratio is unity or greater (p<0.01). This method offers time and resource-sparing advantages to ascertaining metabolite exposure comparisons between humans and laboratory animal species. A strategy for application of this approach within standard drug development processes is described.
This article was published in the following journal.
Name: Drug metabolism and disposition: the biological fate of chemicals
Baclofen is actually used to manage alcohol dependence. This study describes a simple method using liquid chromatography coupled to high resolution mass spectrometry (LC-HR-MS) developed in plasma sam...
A simple LC-MS/MS method facilitated by salting-out assisted liquid-liquid extraction (SALLE) to simultaneously determine trans-resveratrol (Res), its glucuronide and sulfate conjugates in rat plasma and its application to pharmacokinetic assay.
A simple LC-MS/MS method facilitated by salting-out assisted liquid-liquid extraction (SALLE) was applied to simultaneously investigate pharmacokinetics of trans-resveratrol (Res), its major glucuroni...
A fully valid ultra-high performance liquid chromatography coupled with mass spectrometry (UHPLC- MS/MS) method was developed for the determination of etoposide, gemcitabine, vinorelbine and their met...
The aim of the present report was to develop and validate simple, sensitive and reliable LC-MS/MS method for quantification of topiramate (TPM) and its main metabolites: 2,3-desisopropylidene TPM, 4,5...
In the present study, a novel sample preparation method based on magnetic core-mesoporous shell microspheres with C8-modified interior pore walls (C8-Fe3O4@mSiO2) was established for the identificatio...
The purpose of this study is to evaluate the relative exposures of lofexidine and its major metabolites in subjects seeking buprenorphine dose reduction.
The purpose of this study is: To determine the rate and routes of excretion of BIA 3-202 and the mass balance in urine and faeces To determine the kinetics of total radioactivity in blood...
The primary objectives of the study are: To determine the mass balance and routes of elimination of BIIB074 and its known metabolites following administration of a single oral dose of BIIB...
The purpose of the study is to examine the individual metabolic profiles of pediatric patients receiving carbamazepine or valproate therapy, in an attempt to determine identities of the re...
The purpose of this study is to investigate the kinetics of two known alkylresorcinol metabolites in human subjects after intake of high-fiber rye bread. Whole grain rye is the most abunda...
The method of measuring the dispersion of an optically active molecule to determine the relative magnitude of right- or left-handed components and sometimes structural features of the molecule.
An alpha-globulin found in the plasma of man and other vertebrates. It is apparently synthesized in the liver and carries vitamin D and its metabolites through the circulation and mediates the response of tissue. It is also known as group-specific component (Gc). Gc subtypes are used to determine specific phenotypes and gene frequencies. These data are employed in the classification of population groups, paternity investigations, and in forensic medicine.
A method of studying a drug or procedure in which both the subjects and investigators are kept unaware of who is actually getting which specific treatment.
A spectrum of clinical liver diseases ranging from mild biochemical abnormalities to ACUTE LIVER FAILURE, caused by drugs, drug metabolites, and chemicals from the environment.
A spectrum of clinical liver diseases ranging from mild biochemical abnormalities to ACUTE LIVER FAILURE, caused by drugs, drug metabolites, herbal and dietary supplements and chemicals from the environment.
Blood is a specialized bodily fluid that delivers necessary substances to the body's cells (in animals) – such as nutrients and oxygen – and transports waste products away from those same cells. In vertebrates, it is composed of blo...
Clinical Approvals Clinical Trials Drug Approvals Drug Delivery Drug Discovery Generics Drugs Prescription Drugs In the fields of medicine, biotechnology and pharmacology, drug discovery is the process by which drugs are dis...