Unique human metabolites

Unique Human Metabolites The FDA draft guidance document defines the term as a metabolite only in humans. The MIST document refers to a unique human metabolite as a metabolite identified in the plasma of humans but not in animals. However, it is very rare to find a truly unique human metabolite that is not formed in any animal species (Davis-Bruno and Atrakchi, 2006). 

Unique Human Metabolites The FDA metabolite safety testing guidance indicates that the unique human metabolite(s) should be considered for safety assessment in animals, especially those that have pharmacological activity or associated with a structural alert. However, there are some situations where a full set of safety studies for unique human metabolites may not be necessary, such as if the metabolite is very minor in human plasma or it is only found in human feces. 

Early identification of unique or major human metabolites can provide clear directions for testing in animals, assist in interpreting and planning of clinical studies, and prevent delays in drug development/ approval. 

The metabolome refers to the entire collection of metabolites, including lipids, sugars, amino acids, and nucleosides within an organism [2]. Though there is still some debate as to the exact number of metabolites, the current estimate is 6,800 human metabolites [25]. Compared to large biopolymers consisting of thousands of atoms, such as proteins and nucleic acids, the structures of many metabolites seem simple. However, this simplicity masks the unique challenge associated with analysis of the metabolome due to the distinct physicochemical properties of different classes of metabolites. For example, the isolation and analysis protocols... 

Cone, E. J., Yousefnejad, D., Darwin, W. D., and Maguire, T., Testing human hair for drugs of abuse. II. Identification of unique cocaine metabolites in hair of drug abusers and evaluation of decontamination procedures,/. Ana/. Toxicol, 15, 250,1991. 

As in many fields of research, new tools and techniques for measuring carotenoids in various systems are critical to support research progress. Several chapters discuss new methodologies to measure carotenoids (see Chapter 4), carotenoid metabolites/radicals (see Chapter 9), or carotenoids in vivo in complex biological systems, especially in the human eye (e.g., see Chapters 5 and 6). Other chapters describe the oxygenase enzymes that are essential components of carotenoid metabolism to active metabolites (see Chapter 19). The study of active metabolites includes the in-depth evaluation of carotenoid cleavage products (see Chapter 11) and carotenoid radicals (see Chapter 14) that may account for some of the biological actions observed for these unique substances. 

While comparatively few dihydrodiols have been observed in the metabolism of phenyl-containing drugs, the examples above are far from unique. Thus, oxazepam incubated in rat, mouse, and human microsomes did yield a dihydrodiol besides the para-phenol [82], A more-recent example is that of rofecoxib (10.22), a potent and selective cyclooxygenase-2 (COX-2) inhibitor. In rats and dogs, phenyl oxidation produced 4 -hydroxyrofecoxib and rof-ecoxib-3, 4 -dihydrodiol as urinary metabolites of intermediate quantitative importance [83]. 

This lack of information may well relate to bupropion s complex metabolism, whereby biologically active metabolites predominate several-fold over the parent compound these metabolites may ultimately prove to be the basis for therapeutic effects [Golden et al. 1988]. Furthermore, because the full spectrum of action of the metabolites has not been explored, it is difficult to confidently characterize the primary biochemical action of bupropion as noradrenergic. One must therefore be cautious in interpreting any distinct aspects of bupropion s clinical actions as reflecting some noradrenergic mechanisms. And to our knowledge, bupropion is unique in that no other compound available for use in humans has a similar overall profile of preclini-cal and clinical biochemical effects. 

The polychlorinated androstanes clionastatins A (659) and B (660) were isolated from the burrowing sponge Cliona nigricans (Fig. 3.10) collected in two locations along the Italian coast (761). These unique metabolites have good cytotoxic activity against murine and human cancer cell lines. The eastern Pacific octocoral Carijoa multiflora has yielded the unusual chlorinated pregnanes 661 and 662 in a chloroform-free isolation process (762). 

If a unique or human specific metabolite is observed during in vitro cross-species comparison studies, additional toxicological studies are warranted. 

If a unique or human specific circulating metabolite is absent or present at relatively low concentration in toxicological species, separate studies to evaluate the toxicity of the human specific metabolite are warranted. 

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