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CHAPTER 4 Drug Biotransformation 57

have extremely long half-lives if it were not for their metabolic O H
conversion to more water-soluble compounds.
Metabolic products are often less pharmacodynamically active N C N NH 2 (INH)
than the parent drug and may even be inactive. However, some bio- Phase II (acetylation)
transformation products have enhanced activity or toxic properties.
It is noteworthy that the synthesis of endogenous substrates such as O H H O
steroid hormones, cholesterol, active vitamin D congeners, and bile
acids involves many pathways catalyzed by enzymes associated with N C N N C CH 3 (N-acetyl INH)
the metabolism of xenobiotics. Finally, drug-metabolizing enzymes
have been exploited in the design of pharmacologically inactive Phase I (hydrolysis)
prodrugs that are converted to active molecules in the body. O O H
N C OH + CH 3 C N NH (acetylhydrazine)
2
THE ROLE OF BIOTRANSFORMATION IN
DRUG DISPOSITION Isonicotinic acid Acetylation of
macromolecules
(proteins)
Most metabolic biotransformations occur at some point between Hepatotoxicity
absorption of the drug into the circulation and its renal elimination.
A few transformations occur in the intestinal lumen or intestinal FIGURE 4–2 Phase II activation of isoniazid (INH) to a hepatotoxic
wall. In general, all of these reactions can be assigned to one of two metabolite.
major categories called phase I and phase II reactions (Figure 4–1).
Phase I reactions usually convert the parent drug to a more N-acetyl conjugate in a phase II reaction. This conjugate is then
polar metabolite by introducing or unmasking a functional group a substrate for a phase I type reaction, namely, hydrolysis to
(–OH, –NH , –SH). Often these metabolites are inactive, although isonicotinic acid (Figure 4–2). Thus, phase II reactions may actually
2
in some instances activity is only modified or even enhanced. precede phase I reactions.
If phase I metabolites are sufficiently polar, they may be readily
excreted. However, many phase I products are not eliminated rap-
idly and undergo a subsequent reaction in which an endogenous WHERE DO DRUG
substrate such as glucuronic acid, sulfuric acid, acetic acid, or an BIOTRANSFORMATIONS OCCUR?
amino acid combines with the newly incorporated functional
group to form a highly polar conjugate. Such conjugation or Although every tissue has some ability to metabolize drugs, the
synthetic reactions are the hallmarks of phase II metabolism. A liver is the principal organ of drug metabolism. Other tissues that
great variety of drugs undergo these sequential biotransformation display considerable activity include the gastrointestinal tract, the
reactions, although in some instances, the parent drug may already lungs, the skin, the kidneys, and the brain. After oral administration,
possess a functional group that may form a conjugate directly. For many drugs (eg, isoproterenol, meperidine, pentazocine, morphine)
example, the hydrazide moiety of isoniazid is known to form an are absorbed intact from the small intestine and transported first

Absorption Metabolism Elimination

Phase I Phase II
Drug Conjugate
Drug metabolite with
modified activity Conjugate
Drug
Inactive drug
metabolite Conjugate
Drug

Lipophilic Hydrophilic

FIGURE 4–1 Phase I and phase II reactions, and direct elimination, in drug biodisposition. Phase II reactions may also precede phase I
reactions.