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THE ROLE OF BIOTRANSFORMATION IN DRUG DISPOSITION
Most metabolic biotransformations occur at some point between absorption of the drug into the general circulation and its renal elimination. A few transformations occur in the intestinal lumen or intestinal wall. In general, all of these reactions can be assigned to one of two major categories called phase I and phase IIreactions (Figure 4–1).
Phase I reactions usually convert the parent drug to a more polar metabolite by introducing or unmasking a functional group (−OH, −NH2, −SH). Often these metabolites are inactive, although in some instances activity is only modified or even enhanced.
If phase I metabolites are sufficiently polar, they may be readily excreted. However, many phase I products are not eliminated rapidly and undergo a subsequent reaction in which an endoge-nous substrate such as glucuronic acid, sulfuric acid, acetic acid, or an amino acid combines with the newly incorporated functional group to form a highly polar conjugate. Such conjugation or syn-thetic reactions are the hallmarks of phase II metabolism. A great variety of drugs undergo these sequential biotransformation reac-tions, although in some instances the parent drug may already possess a functional group that may form a conjugate directly. For example, the hydrazide moiety of isoniazid is known to form an N-acetyl conjugate in a phase II reaction. This conjugate is then asubstrate for a phase I type reaction, namely, hydrolysis to isonico-tinic acid (Figure 4–2). Thus, phase II reactions may actually precede phase I reactions.
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