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The overall fate or disposition of a xenobiotic, which encompasses its absorption, distribution, metabolism, and elimination or ADME (an acronym commonly used by the pharmaceutical industry), is determined by three major factors, namely passive diffusion across biological membranes or between cells (i.e., transcellular and paracellular passive diffusion, respectively), facilitated transport by uptake and/or efflux transporters, and biotransformation (invariably called metabolism in the case of drugs). In the case of xenobiotics that permeate cells with a high rate of passive diffusion, which enables them to be absorbed from the gastrointestinal tract, lung, or skin (depending on the route of exposure), biotransformation plays a key role in their elimination. Without biotransformation, a highly permeable xenobiotic excreted in urine or bile will be reabsorbed in the kidney or intestine rather than eliminated in urine or feces. If a xenobiotic can permeate cells with a high rate of passive diffusion but it cannot be biotransformed at an appreciable rate then the xenobiotic can have a long residency time in the body. Dioxin (2,3,7,8-tetracholorodibenzo-p-dioxin or TCDD) illustrates this principle. Dioxin permeates cells with a high rate of passive diffusion, but it is largely resistant to biotransformation. For this reason, dioxin and numerous other polyhalogenated aromatic hydrocarbons (PCDFs, PCBs, PBBs, etc.), industrial chemicals present in the environment, are renowned for their persistence in the body and for their bioaccumulation in the food chain. The lesson from dioxin and related compounds, namely that halogenation is not an obstacle to passive permeation but is an obstacle to biotransformation, is not lost on the pharmaceutical industry. Many drugs are fluorinated (and some are chlorinated, brominated or iodinated) at metabolically labile sites to slow their rate of biotransformation and thereby prolong their residency time in the body in order to extend their therapeutic effect, which may make once-a-day dosing at a low dose feasible (Obach et al., 2016).

In all previous versions of this chapter, biotransformation has been described as an enzymatic process of chemical modification that changes the physicochemical properties of a xenobiotic from those that favor absorption and distribution (i.e., high passive permeability associated with high lipophilicity) to those that favor elimination (i.e., low passive permeability associated with high hydrophilicity). This rationalization of biotransformation is still valid but it overlooks an important principle, namely that facilitated transport also plays a key role in the disposition of xenobiotics, including those whose elimination is determined by their rate of biotransformation. Facilitated transport resolves a conundrum that has long been overlooked in drug metabolism circles: If biotransformation converts a lipophilic xenobiotic to hydrophilic metabolites, how do the hydrophilic metabolites get out of the cell that forms them? The short answer is: They are transported out of the cell. In many cases transporters play an important role in the elimination of drugs whose systemic clearance is primarily determined by their rate of biotransformation in the liver. The opposite is also true: In many cases biotransformation plays an ...

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