Metabolic scopes for activity

Figure 2.5. Metabolic scope for activity (defined as the difference between maximum metabolic rate and the SMR) and the metabolic scope for survival (defined as the difference between the SMR and maximally suppressed metabolic rates). Hummingbird estimates shown for normothermic conditions and for torpor metabolic rates (the latter gives the full biological scope for activity). Suppressed metabolic rates for the aquatic organisms assume temperatures of about 20°C (except for the pumpkinseed, where suppressed metabolism occurs during overwintering hibernation at about 4°C). (Modified from Hochachka (1990.)...

In this book we will focus on physicochemical profiling in support of improved prediction methods for absorption, the A in ADME. Metabolism and other components of ADME will be beyond the scope of this book. Furthermore, we will focus on properties related to passive absorption, and not directly consider active transport mechanisms. The most important physicochemical parameters associated with passive absorption are acid-base character (which determines the charge state of a molecule in a solution of a particular pH), lipophilicity (which determines distribution of a molecule between the aqueous and the lipid environments), solubility (which limits the concentration that a dosage form of a molecule can present to the solution and the rate at which the molecule dissolves from... 

These are often very difficult tasks because chemical development is usually drawn into its API supply mission at a very early juncture. At the start of a program there are many uncertainties to resolve before identifying the most desirable API structure and scoping out the market opportunities. Is the desirable API one of several chiral options Is the desired activity associated with the API as synthesized, or one of its metabolites The corollary of this is, Will the API structure need to be modified to prevent an unwanted metabolic conversion—often by substitution of the metabolic site (e.g., an H atom may be replaced by F) Will the API need to be delivered in an oral, topical, parenteral, or inhalation form, or more than one of these Once selected, will the desired API be a salt or a pro-drug Even then there will be questions as to which salt or what structure will be selected for the pro-drug moiety. Inevitably,... 

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