Safety Testing of Drug Metabolites: Mist Guidance Impact on the Practice of Industrial Drug Metabolism

Slatter, J. Greg

doi:10.1002/9780470890387.ch8

Cited by 3 publications

(6 citation statements)

References 39 publications

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“…The 13 C drug and metabolites, incubated separately, were simply assumed to be 'similar' in concentration and since the absolute amount added is not important over some 'usable' range, this assumption worked very well. A second, and we argue easier, approach is to metabolize each standard, 12 C, 13 C, and C incubate can be directly calculated using peak areas. Again, the 13 C drug and metabolites were simply assumed to be 'similar' in concentration.…”

Section: Resultsmentioning

confidence: 99%

“…A second, and we argue easier, approach is to metabolize each standard, 12 C, 13 C, and C incubate can be directly calculated using peak areas. Again, the 13 C drug and metabolites were simply assumed to be 'similar' in concentration. Figure 4 displays a representative standard curve using HRID.…”

Section: Resultsmentioning

confidence: 99%

“…We viewed quantitative analysis by HRMS to be far simpler than analysis by tandem quadrupole MS, especially in view of the instrument manufacturer's recent attention to combining qualitative and quantitative analysis applications for LC/HRMS instruments, and our conclusion was that the approach described herein should be investigated for ruggedness and ease of development. Note: The authors do appreciate that this experiment could be accomplished without 13 C, but using 14 C alone, provided that the analysis is at a high enough resolution to differentiate the A+2 ion derived from one 14 C and two 13 C. This will hopefully be the subject of a subsequent manuscript. We also appreciate the fact that tritium could be used in place of 14 C, in specific situations.…”

Section: Idms With High-resolution Mass Spectrometry (Hrms)mentioning

confidence: 99%

“…Issues surrounding this calculation were clearly outlined by Slatter recently. [13] Editorial comments aside, these are the rules we operate under: The Guidances increase, on average, the number of quantitative analysis methods needed in drug development and, therefore, the Guidances have increased our work load. Quantitative HRMS.…”

Section: Idms With High-resolution Mass Spectrometry (Hrms)mentioning

confidence: 99%

“…Additional considerations (motivations). Other considerations were that: (a) We work in a changing research climate (CRO) that now allows for the purchase of the ]-labeled compound (e.g., the only change in the synthesis process is to request that enough 13 C x compound is made, and that the number of 13 C atoms and the atoms percent purity relative to the A ion is appropriate, to conduct the studies we have described). Another important consideration is the ease with which plated human hepatocytes can be obtained and kept viable for many days.…”

Section: Idms With High-resolution Mass Spectrometry (Hrms)mentioning

confidence: 99%

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High‐resolution isotope‐dilution mass spectrometry using metabolism of isotope‐labeled compounds: Application to drug metabolites

Vrbanac

Hilgers

Dubnicka

et al. 2012

Rapid Comm Mass Spectrometry

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RATIONALE: Herein we describe a generic quantitative method using high-resolution, isotope-dilution (HRID) metabolism of isotope-labeled compounds and apply it to the analysis of drug metabolites (DMs) in human plasma. Metabolites (drug) 0 HD were used to make standard curves. Plasma samples were prepared by 'dilute-and-shoot' and analyzed by LC/MS using SCIEX 5000 and Thermo Orbitrap instrumentation. RESULTS: Human hepatic microsomes and the S9 fraction produced between 2-6 mM b-hydroxy-T and 4 0 -hydroxy-D at 60 min starting with 10 mM parent drug as determined by LC/RAM. It was assumed that the amounts of [ The study of the movement (disposition) of molecules and atoms in vivo is constrained by the analytical techniques applicable to a particular structure; however, the approach of labeling with radioisotopes and stable isotopes to study endogenous compounds (endobiotics) and xenobiotics (drugs) offers obvious advantages and has been widely applied in biochemical research. In pharmacology, quantitative (kinetic) and qualitative analysis of the radioactive constituents in tissues and fluids in vivo and in excreta following administration of a 14 C-labeled drug is a standard protocol required for drug development and registration (radiolabeled distribution, or 'mass balance', and metabolism study; the quantitative and qualitative analysis of drug-related material). Far earlier in the drug discovery and development process, questions related to the biotransformation of drugs occur and these include: (1) What are the rates of metabolism across species in vitro and in vivo and what is the role of metabolism in drug clearance (CL), and (2) What is the qualitative nature of the drug metabolite profile including formation of reactive metabolites? It is important to determine not only the qualitative nature of the drug metabolic profile, but to also make a reasonable estimate of the amounts of drug metabolites produced in preclinical species and in man. This estimate of exposure to drug metabolites should be viewed in the context of both (1) exposure relative to other drug-related material (parent alone or sum of drug-related material), a percentage, and (2) exposure in an absolute sense, such as mM concentrationtime in plasma data. In specific situations, the accurate quantitative analysis of drug metabolites is important.For situations where the quantitative analysis of drug metabolites is warranted, there are two general approaches that are commonly employed. The first approach is to obtain an authentic standard for the drug metabolite (DM) and use the standard in the conventional manner. In this process, the structures of DMs are partially characterized and authentic standards synthesized (full structural characterization), and a quantitative analytical method developed using an authentic standard. This is an expensive and time-consuming process, although the use of cloned-expressed enzymes followed by purification of product has streamlined the process somewhat and certainly affords considerable cost containmen...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Idms With High-resolution Mass Spectrometry (Hrms)mentioning

confidence: 99%

Section: Idms With High-resolution Mass Spectrometry (Hrms)mentioning

confidence: 99%

Section: Idms With High-resolution Mass Spectrometry (Hrms)mentioning

confidence: 99%

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High‐resolution isotope‐dilution mass spectrometry using metabolism of isotope‐labeled compounds: Application to drug metabolites

Vrbanac

Hilgers

Dubnicka

et al. 2012

Rapid Comm Mass Spectrometry

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Safety Testing of Drug Metabolites: A Practical Approach for the Implementation of the MIST Guidance in PKDM

Subramanian

Slatter

2012

Encyclopedia of Drug Metabolism and Interactions

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The FDA Safety Testing of Drug Metabolites Guidance and the ICH Requirements for Registration of Pharmaceuticals for Human Use (ICH M3) guidance defined threshholds for metabolite exposure in humans and preclinical species, which (ICH M3) would indicate that preclinical species were exposed adequately to quantitatively significant human metabolites. Proactive, data‐driven, best practices were developed by consensus with key development partners. Nontraditional metabolism approaches such as nonradiometric high resolution‐mass spectrometry (HR‐MS) profiling of plasma metabolites across species were developed to enable timely drug development decision making.

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Overview of ADME Science

Vrbanac,

Slauter

2024

A Comprehensive Guide to Toxicology in Nonclinical Drug Development

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Safety Testing of Drug Metabolites: Mist Guidance Impact on the Practice of Industrial Drug Metabolism

Cited by 3 publications

References 39 publications

High‐resolution isotope‐dilution mass spectrometry using metabolism of isotope‐labeled compounds: Application to drug metabolites

High‐resolution isotope‐dilution mass spectrometry using metabolism of isotope‐labeled compounds: Application to drug metabolites

Safety Testing of Drug Metabolites: A Practical Approach for the Implementation of the MIST Guidance in PKDM

Overview of ADME Science

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