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
Pretreatment of plasma samples by a novel hollow fiber centrifugal ultrafiltration technique for the determination of plasma protein binding of three coumarins using acetone as protein binding releasing agent.
A novel and practical sample pretreatment method based on hollow fiber centrifugal ultrafiltration (HFCF-UF) was developed to determine plasma protein binding by using HPLC. The samples for analyzing ...
Development of analytical method for simultaneous determination of five rodent unique bile acids in rat plasma using ultra-performance liquid chromatography coupled with time-of-flight mass spectrometry.
Bile acids (BAs) are crucial for the diagnosis, follow-up, and prognostics of liver injuries and other BA metabolism related diseases. In particular, rodent unique BAs, α-muricholic acid (α-MCA), β...
Understanding the fate of metallodrugs in the bloodstream is critical to assess if the parent drug has a reasonable probability to reach the intended target tissue and to predict toxic side-effects. T...
Andrographis paniculata contains four major active diterpenoids, including andrographolide (1), 14-deoxy-11, 12-didehydroandrographolide (2), neoandrographolide (3), and 14-deoxyandrographolide (4), w...
The U.S. Department of Energy Standard 3009-2014 requires one of two methods to determine the simple Gaussian relative concentration (X/Q) of pollutant at plume centerline downwind to a receptor for a...
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 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 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 study will be an open-label, randomized, 2-period, 2-treatment, 2-sequence, cross-over, single-dose study employing administration of two PF-02341066 formulations in the fasted state t...
Objectives: Plasma levels of catechols have distinct meanings in terms of indicating functions of endogenous catecholamine systems. This Protocol is designed to enable ongoing quality assu...
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.
Drugs and their metabolites which are found in the edible tissues and milk of animals after their medication with specific drugs. This term can also apply to drugs found in adipose tissue of humans after drug treatment.
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...