A SIMPLE LC/MS/MS METHOD TO DETERMINE RELATIVE PLASMA EXPOSURES OF DRUG METABOLITES ACROSS SPECIES FOR METABOLITE SAFETY ASSESSMENTS (MIST).

17:08 EDT 1st September 2014 | BioPortfolio

Summary of "A SIMPLE LC/MS/MS METHOD TO DETERMINE RELATIVE PLASMA EXPOSURES OF DRUG METABOLITES ACROSS SPECIES FOR METABOLITE SAFETY ASSESSMENTS (MIST)."

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.

Affiliation

Pfizer, Inc.

Journal Details

This article was published in the following journal.

Name: Drug metabolism and disposition: the biological fate of chemicals
ISSN: 1521-009X
Pages:

Links

PubMed Articles [31098 Associated PubMed Articles listed on BioPortfolio]

Simultaneous LC-MS/MS quantification of P-glycoprotein and cytochrome P450 probe substrates and their metabolites in DBS and plasma.

Background: An LC-MS/MS method has been developed for the simultaneous quantification of P-glycoprotein (P-gp) and cytochrome P450 (CYP) probe substrates and their Phase I metabolites in DBS and plasm...

Simple and sensitive method for the analysis of ketorolac in human plasma using high-performance liquid chromatography.

To develop a simple and sensitive method of ketorolac in drug free human plasma using high-performance liquid chromatographic (HPLC).

Simultaneous determination of imperatorin and its metabolites in vitro and in vivo by a GC-MS method: application to a bioavailability and protein binding ability study in rat plasma.

In this study, a simple and sensitive gas chromatography-mass spectrometry method was developed for the study of bioavailability and protein binding and the metabolism of imperatorin in rat. The resul...

Simple and sensitive analysis of blonanserin and blonanserin C in human plasma by liquid chromatography tandem mass spectrometry and its application.

A highly sensitive, simple, and rapid liquid chromatography tandem mass spectrometry method to simultaneously determine blonanserin and blonanserin C in human plasma with AD-5332 as internal standard ...

Quantification and validation of ertapenem using a liquid chromatography-tandem mass spectrometry method.

Background:Ertapenem, a carbapenem, relies on time-dependant killing. Therapeutic drug monitoring (TDM) should be considered, when used in specific populations, to achieve optimal bactericidal activit...

Clinical Trials [4205 Associated Clinical Trials listed on BioPortfolio]

Plasma Pharmacokinetics of Alkylresorcinol Metabolites; New Candidate Biomarkers for Whole Grain Rye and Wheat Intake

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...

Pathogenesis of Adverse Drug Reactions

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...

Relative Drug Exposures Of Two Formulations of PF-02341066

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...

Reference Values for Plasma Catechols

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...

A Study of Plasma Concentrations, Metabolism and Excretion of 14C-paliperidone After a Single Oral Dose

The purposes of this study are to investigate the metabolic pathways of paliperidone and excretion of paliperidone and its metabolites in healthy adult male volunteers, both CYP2D6 poor an...

Medical and Biotech [MESH] Definitions

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.

Search BioPortfolio:
Advertisement

Relevant Topic

Blood
Latest News Clinical Trials Research Drugs Reports Corporate
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...

Advertisement