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  • To outline the major pathways of drug biotransformation mediated by phase II enzymes.
  • To define the properties and multiplicity of genes that encode phase II biotransformation enzymes.
  • To emphasize the extent of genetic variation in important genes that mediate phase II drug biotransformation.
  • To provide established examples of pharmacogenetic variants in phase II drug-metabolizing enzymes that influence drug therapy.
  • To evaluate the evidence for additional examples of pharmacogenetic variation in drug-metabolizing enzymes that influence therapeutic outcomes with drugs.

Role of Phase II Biotransformation in Drug Elimination

There is often a high concordance between the pharmacokinetic properties of drugs and their therapeutic actions. Serum concentrations are frequently used as surrogate markers for the likely concentrations of drugs achieved at the site of action in tissues. Rates of drug biotransformation and elimination are critical factors that influence the serum concentrations of drugs and their duration of action in the body. Rapid drug clearance may lead to subtherapeutic concentrations in tissues that diminishes efficacy. On the other hand, if clearance is impaired, drugs may accumulate and produce toxicity.

Like other xenobiotics, drugs are generally quite hydrophobic and undergo biotransformation to polar products following the concerted actions of several families of drug-metabolizing enzymes; this process enhances clearance. In phase I metabolism a functional group is introduced into the parent molecule that renders the drug more polar. However, the aqueous solubility of many phase I metabolites may be inadequate for efficient elimination. In phase II biotransformation reactions these phase I metabolites of intermediate polarity as well as parent drug undergo conjugation with highly polar endogenous molecules. This markedly increases aqueous solubility and the resultant drug conjugates are eliminated more readily in urine or feces. Thus, phase II biotransformation pathways usually mediate the terminal phase of the removal of drugs and other foreign compounds from the body.

Enzymes of Phase II Biotransformation

There are several classes of phase II biotransformation enzymes that catalyze drug conjugation reactions (Table 6B–1 lists these enzymes and those that mediate the formation of essential cofactors). Among the most important are the UDP-glucuronosyltransferases (UGTs), sulfotransferases (SULTs), N-acetyltransferases (NATs), and glutathioneS-transferases (GSTs). Together these enzymes contribute to the majority of clearance pathways that exist for most drugs. Additional phase II enzymes include thiopurine S-methyltransferase (TPMT) and the acyl-CoA synthetase medium-chain family members that act in conjunction with acyl-CoA:amino acid N-acyltransferases to generate amino acid conjugates. While not widely involved in drug biotransformation, some of these enzymes have roles in the clearance of a limited number of therapeutic agents. Finally, there is a group of enzymes such as catechol O-methyltransferase (COMT) and other methyltransferases that are functionally important in the clearance of neurotransmitters or other molecules of endogenous importance. Some studies have suggested that these enzymes participate in drug clearance but the supportive clinical evidence that currently exists is inconclusive.

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