In modern pharmaceutical development, early screening is done with new
candidate drugs for the nature of metabolites, identification of enzymes
involved, induction, and inhibition. A general goal is to have only limited
induction and inhibition and to have several enzymes involved in the initial
attack on the drug (but slowly enough to maintain acceptable bioavailability
and drug half-life). A major contribution of a highly polymorphic enzyme is
considered undesirable.
A final point is that most of the reactions have the effect of deactivating
drugs. In a few cases a product will have more of the desired pharmacological
activity (i.e., ‘‘prodrugs’’). A concern is that some reactions yield electrophilic
‘‘reactive’’ metabolites that can produce toxicity.
2.4 FRACTIONAL CONTRIBUTIONS OF DIFFERENT ENZYMES
The number of enzymes involved in drug metabolism is large and the number
of possibilities with a new drug can be bewildering. A perspective on the roles
of enzymes is shown in Fig. 2.1a (Williams et al., 2004). Of the enzymes
participating in the metabolism of drugs, the dominant players (75%) are the
P450 enzymes, followed by UDP-glucuronosyltransferases (covered in the next
chapter) and esterases. Together, these reactions account for95% of drug
metabolism. A further breakdown of the P450 enzymes is presented in
Fig. 2.1b, with five of the P450s accounting for90% of the reactions. A single
P450, P450 3A4, is involved in about half of these reactions (Guengerich, 1999;
Rendic, 2002). Although the contributions of other enzymes are less, they
cannot be ignored and may be critical in many cases. The overall patterns
shown in Fig. 2.1 have not changed considerably in recent years (Wrighton and
Stevens, 1992), although a diminution of the roles of the polymorphic P450s
FIGURE 2.1 (a) Fractions of drugs metabolized by various enzyme systems.
(b) Fractions of drugs that are P450 substrates metabolized by individual P450s.
(Adapted with permission from Williams et al., 2004).
FRACTIONAL CONTRIBUTIONS OF DIFFERENT ENZYMES 17