WHY IS DRUG BIOTRANSFORMATION
NECESSARY?
Renal
excretion plays a pivotal role in terminating the biologic activity of some
drugs, particularly those that have small molecular volumes or possess polar
characteristics, such as functional groups that are fully ionized at
physiologic pH. However, many drugs do not possess such physicochemical
properties. Pharma-cologically active organic molecules tend to be lipophilic
and remain unionized or only partially ionized at physiologic pH; these are
readily reabsorbed from the glomerular filtrate in the nephron. Certain
lipophilic compounds are often strongly bound to plasma proteins and may not be
readily filtered at the glomeru-lus. Consequently, most drugs would have a
prolonged duration of action if termination of their action depended solely on
renal excretion.An alternative process that can lead to the termination or
alteration of biologic activity is metabolism. In general, lipophilic
xenobiotics are transformed to more polar and hence more readily excreted
products. The role that metabolism plays in the inactiva-tion of lipid-soluble
drugs can be quite dramatic. For example, lipophilic barbiturates such as
thiopental and pentobarbital would have extremely long half-lives if it were
not for their metabolic conversion to more water-soluble compounds.Metabolic
products are often less pharmacodynamically active than the parent drug and may
even be inactive. However, some biotransformation products have enhanced activity or toxic prop-erties.
It is noteworthy that the synthesis of endogenous sub-strates such as steroid
hormones, cholesterol, active vitamin D congeners, and bile acids involves many
pathways catalyzed by enzymes associated with the metabolism of xenobiotics.
Finally, drug-metabolizing enzymes have been exploited in the design of
pharmacologically inactive prodrugs that are converted to active molecules in
the body.
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