ADME Studies in Animals and Humans: Experimental Design, Metabolite Profiling and Identification, and Data Presentation

Pharmacologically Active Drug Metabolites: Impact on Drug Discovery and Pharmacotherapy

“…A lengthy discussion of how drug metabolites are identified is beyond the scope of this review and the interested reader is referred to other descriptions of this topic for greater depth (Prakash et al, 2007;Zhang and Comezoglu, 2007). However, to understand the issue of pharmacologically active metabolites, a very brief description of how metabolites are identified is necessary.…”

Integrated strategies for assessment of metabolite exposure in humans during drug development: analytical challenges and clinical development considerations

“…Radioactivity analysis and metabolite identification in ADME studies are routinely performed using existing analytical tools and expertise in most drug metabolism laboratories [10]. A radiolabel not only facilitates metabolite detection, but also provides excellent metabolite quantitation in plasma, which is especially effective in the analysis of multiple metabolites at low concentrations [11]. Radioactivity profiling data can serve for calculating relative abundances of metabolites (% of the total drugrelated materials or % of the parent drug) and absolute concentration of plasma metabolites.…”

“…The assessment of metabolite exposure in humans and toxicology animals requires significant efforts. Historically speaking, a radiolabeled human ADME study provides initial information on metabolite exposure in humans [10,11]. Major plasma metabolites are then isolated for structural elucidation by mass spectrometry and NMR; the metabolites are subsequently monitored in clinical and non-clinical studies using validated bioanalytical methods with synthetic reference standards.…”

Development and validation of a gas chromatography/mass spectrometry method for simultaneous quantification of benzylpiperazine and its metabolites: Application to a pilot toxicokinetic study in mice

“…The primary objective of toxicokinetic studies is to describe the systemic exposure after a drug administration through the evaluation of drug's absorption, distribution, metabolism, and excretion (ADME) (108,109). These studies are important to correctly understand the pharmacology and toxicology of any given compound, and are performed both in vivo and in vitro.…”

“…These studies are important to correctly understand the pharmacology and toxicology of any given compound, and are performed both in vivo and in vitro. The in vivo studies due to ethical issues are normally performed in animals, and will allow the (i) validation of toxicological species, (ii) identification of the major metabolic pathways, (iii) assessment of drug-drug interactions, (iv) determination of the rate and excretion pathway(s), and (v) evaluation of the distribution of the compound and metabolites in the body which helps to understand their toxicity and/or pharmacological effects (109). Thus, toxicokinetic studies are a part of the assessment of the risk and safety of compounds (110).…”