A MIST conception: what has been learned from twenty years of human metabolite safety assessment?

Luffer‐Atlas, Debra; Obach, R. Scott; Smith, Dennis A.

doi:10.1007/s00044-023-03089-9

Cited by 4 publications

(4 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The authors of this paper suggest using an expected threshold of > 25% of metabolic clearance as a compromise between what is practically feasible and what is acceptable from a risk perspective. However, even if the extent of the cleavage pathway is low in excreta or maybe not even observed, this does not exclude that a cleavage product may be observed in plasma and potentially be MIST relevant ("Metabolites In Safety Testing"; ICH M3 (R2)) [Leclercq et al, 2009;Luffer-Atlas et al, 2023].…”

Section: When More Than One Label Is Recommendedmentioning

confidence: 99%

“…It is, however, critical that suitable analytical approaches are applied since the mass spectrometry response of cleavage products can be very different from that of the unchanged drug, which can lead to an underprediction of their abundance. [Leclercq et al, 2009;Luffer-Atlas et al, 2023] If the metabolism pathway of the cleavage products is unknown (not already described in literature), more than one label is recommended. However, if one of the cleavage products is not expected to be substantially metabolized further, this moiety could potentially be traced by LC-MS quantification and with that avoid the need for labeling of that part of the parent molecule (please refer to the section on "Analytical techniques enabling detection of non-labeled compounds").…”

Section: When More Than One Label Is Recommendedmentioning

confidence: 99%

See 1 more Smart Citation

Recommendations on the Use of Multiple Labels in Human Mass Balance Studies

Cuyckens,

Hvenegaard,

Cassidy

et al. 2024

Drug Metab Dispos

View full text Add to dashboard Cite

The administration of radiolabeled drug candidates is considered the gold standard in absorption, distribution, metabolism and excretion (ADME) studies for small molecule drugs, since it allows facile and accurate quantification of parent drug, metabolites and total drug related material independent of the compound structure. The choice of the position of the radiolabel, typically 14 C or 3 H, is critical to obtain relevant information. Sometimes a biotransformation reaction may lead to cleavage of a part of the molecule. As a result, only the radiolabeled portion can be followed while information on the fate of the non-labeled metabolite may be lost. Synthesis and administration of two or more radiolabeled versions of the parent drug as a mixture or in separate studies may resolve this issue but comes with additional challenges. In this paper we address the questions that may be considered to help make the right choice whether to use single or a multiple radiolabel approach, discuss pros and cons of different multiple labeling strategies that can be taken as well as alternative methods that allow the non-labeled part of the molecule to be followed.

show abstract

Section: When More Than One Label Is Recommendedmentioning

confidence: 99%

Section: When More Than One Label Is Recommendedmentioning

confidence: 99%

Recommendations on the Use of Multiple Labels in Human Mass Balance Studies

Cuyckens,

Hvenegaard,

Cassidy

et al. 2024

Drug Metab Dispos

View full text Add to dashboard Cite

show abstract

“…They have been discovered by chance, from rescuing a drug discovery project, or by designing a prodrug [179]. Chemically reactive or toxic drug metabolites have received increased attention, and the investigation of potential side effects, safety, and toxicity issues of pharmaceutical drug metabolites, which may potentially be formed through biotransformations in the human body, has also evolved with the "Metabolites In Safety Testing" (MIST) guidance and the framework for identifying, quantifying, and assessing human drug metabolite safety [180][181][182]. The investigations of the possible effects of such modified drugs require sufficient amounts of pure drug metabolites; therefore, straightforward methods for their synthetic access are highly desirable and can be highly significant for the timeline of projects.…”

Section: Synthesis Of Pharmaceutical Drug Metabolitesmentioning

confidence: 99%

Synthesis of Metabolites and Metabolite-like Compounds Using Biocatalytic Systems

Wohlgemuth

2023

Metabolites

View full text Add to dashboard Cite

Methodologies for the synthesis and purification of metabolites, which have been developed following their discovery, analysis, and structural identification, have been involved in numerous life science milestones. The renewed focus on the small molecule domain of biological cells has also created an increasing awareness of the rising gap between the metabolites identified and the metabolites which have been prepared as pure compounds. The design and engineering of resource-efficient and straightforward synthetic methodologies for the production of the diverse and numerous metabolites and metabolite-like compounds have attracted much interest. The variety of metabolic pathways in biological cells provides a wonderful blueprint for designing simplified and resource-efficient synthetic routes to desired metabolites. Therefore, biocatalytic systems have become key enabling tools for the synthesis of an increasing number of metabolites, which can then be utilized as standards, enzyme substrates, inhibitors, or other products, or for the discovery of novel biological functions.

show abstract

“…Pharmacologically inactive, or less active by three orders of magnitude, small molecular weight compounds which are enzymatically converted in vivo to the active pharmaceutical have been developed by different paths, either being discovered by chance, from rescueing a drug discovery project, or by designing a prodrug [148]. Chemically reactive or toxic drug metabolites have received increased attention and the investigation of potential side effects, safety and toxicity issues of pharmaceutical drug metabolites which may be potentially be formed by biotransformations in the human body, has also evolved with the "Metabolites In Safety Testing" (MIST) guidance and the framework for identifying, quantifying, and assessing human drug metabolite safety [149][150][151]. As the investigations of the possible effects of such modified drugs require sufficient amounts of pure drug metabolites, straightforward methods for their synthetic access are highly desirable and can be highly significant for the timeline of projects.…”

Section: Synthesis Of Pharmaceutical Drug Metabolitesmentioning

confidence: 99%

Synthesis of Metabolites and Metabolite-Like Compounds Using Biocatalytic Systems

Wohlgemuth

2023

Preprint

View full text Add to dashboard Cite

Methodologies for the synthesis and purification of metabolites, which have been developed following their discovery, analysis and structural identification, have been involved in numerous life science milestones. The renewed focus on the small molecule domain of biological cells has also created an increasing awareness of the rising gap between the metabolites identified and the metabolites which have been prepared as pure compounds. Due to the large number and molecular diversity of metabolites the design and engineering of resource-efficient and straightforward synthetic methodologies for their production have attracted much interest. The variety of metabolic pathways in biological cells provide a wonderful blueprint for designing simplified and resource-efficient synthetic routes to desired metabolites. Therefore, biocatalytic systems have become key enabling tools for the synthesis of an increasing number of metabolites, which can then be utilized as standards, enzyme substrates, inhibitors or products, or for the discovery of novel biological functions.

show abstract

A MIST conception: what has been learned from twenty years of human metabolite safety assessment?

Cited by 4 publications

References 56 publications

Recommendations on the Use of Multiple Labels in Human Mass Balance Studies

Recommendations on the Use of Multiple Labels in Human Mass Balance Studies

Synthesis of Metabolites and Metabolite-like Compounds Using Biocatalytic Systems

Synthesis of Metabolites and Metabolite-Like Compounds Using Biocatalytic Systems

Contact Info

Product

Resources

About