Administration route metabolic activity

One of the most potent carcinogenic polycyclic aromatic hydrocarbons. In animals, large single and multiple doses produce tumors of the skin, breast, and stomach or leukemias, regardless of route of administration. It is a strong mutagen after metabolic activation.2-4... 

The effect of administration route on drug action is discussed in some detail by Benet (19) and by Rowland (20). Oral administration forces a first-pass route through the liver, subjecting the toxicant to enhanced metabolism. Other routes are weaker metabolically, though in some cases, skin can display up to 80% or more of liver metabolite activity. In the rat, for example, skin is more efficient than liver in degrading aryl carbamates. Our results support this thesis in terms of mean Log MW/LD50 values for phenol toxicity but not for carbamate toxicity. 

An active substance generally exerts its effect through defined molecular interactions with a receptor. As a prerequisite, the substance needs to be dissolved and reach the receptor. For a local effect, the substance is usually administered in close proximity to the desired target and should penetrate into body tissues as little as possible. However, when a systemic effect is desired, the substance has to reach the blood circulation system for distribution. For extravascular administration routes, this requires membrane passage and may expose the substance to various pre systemic elimination mechanisms, including metabolism and efflux transporters such as P-glycoprotein. 

Physico-chemical properties of the active substance influence to a large extent the administration routes and dosage forms that are feasible. Relevant properties include solubility, partition coefficient (log P), pKa, membrane passage, metabolic stability, and half-life. Conversely, the administration route and formulation influence safety and efficacy of the active substance. This cause-effect relationship implies that formulations designed for different or even the same route of administration may not be interchangeable. Chapters 4—14 discuss these (im)possibilities in more detail, for different administration routes. 

Cultured mammalian cell systems offer advantages for studying carcinogenesis at the cellular level in the absence of humoral factors that operate in vivo. However, other factors important in animals, such as dose and route of administration, metabolic activation, detoxification by the liver, or transport of organotropic carcinogens to appropriate target sites, must also be considered when in vitro systems are used as predictors of carcinogenicity. 

As mentioned above, bioavailability is the degree to which a drug reaches the intended site of action. The amount of drug that reaches systemic circulation will depend on the processes of absorption, distribution, and biotransformation (when the route of administration exposes the drug to first-pass metabolism). Pharmacokinetics are often linear and when they are nonlinear it is often due to a saturation of protein binding, metabolism, or active renal transport. 

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