Metabolism Issues

Metabolism greatly complicates the drug discovery process. Factors that must be considered include the biological activity of new metabolites, potential interference on metabolism by a drug, and variations in a drug s metabolism across different patient populations. 

The activity of each metabolite formed in the body must be understood and classified into one of three categories  

Many metabolites retain activity from the parent drug, that is, on-target activity. Selected examples of marketed drugs, the major metabolite of each, and the percentage activity of the metabolite are shown in Table 8.1. 

TABLE 8.1 Drugs with metabolites of similar activity11 

Entry Drug Drug Name Metabolite Activity (%) 

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III. Metabolism Issues here include species-specific metabolism (related to novel pattern of drug release at receptor sites), and possible use of novel paracrine- and endocrine-like peptidergic mediators. These could manifest themselves in novel ... 

As far as research collaboration is concerned, the Schering-Plough manufacturing process for its cholesterol absorption inhibitor, Ezetimibe (Zetia), exemplifies the collaboration case. The close interaction between Research and Development, aided by the delay caused by the realization that the first API structure (XVI) had to be modified to overcome metabolism issues, provided the intellectual resource and the time for a fuller understanding of the chemistry needed to create the chiral (3-lactam ring. 

Caco-2 cells are currently used at all levels of pharmaceutical research and development. Automation technologies allow tissue culture labs to easily maintain a large number of Caco-2 cells as well as to perform numerous permeability studies without the introduction of many common human errors. Combinatorial chemistry provides vast arrays of compounds, and Caco-2 assays can be used to assess potential permeability and metabolic issues before much money is invested in the candidate.6... 

As with in vitro estimation of drug absorption, a number of hepatic metabolic issues can be addressed early on in drug discovery and development. These are [10]... 

Assuring Absorption This section will focus upon oral dosing since that is by far the most frequently sought administration protocol for new drugs in general. In this regard, aside from drug metabolism issues and... 

Cobalamin (vitamin B12) a water-soluble B vitamin, normally involved in the human body metabolism, affecting DNA synthesis and regulation, fatty acid synthesis and energy production. Supplied by animal food, its defieiency leads to macrocytic anaemia, decreased bone marrow cell production, neurological problems, as well as metabolic issues (methylmalonyl-CoA acidosis, hyperhomocysteinemia). 

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