these processes and the role they play in the disposition of the drug are
important since they help us understand and predict potential for various types
of interactions, particularly drug–drug interactions. Drugs that are currently
being developed are mainly targeted toward receptors and enzymes and,
therefore, tend to be lipophilic with a molecular weight ranging from 300 to
700 Da. One consequence of selecting compounds with these physicochemical
properties is that most of these drugs are primarily eliminated through
metabolism. Oxidative, hydrolytic, reductive, or conjugative (glucuronidation,
sulfation, etc.) metabolic pathways are often responsible for clearance of
modern drugs (Parkinson, 2001). Oxidative metabolism, mainly catalyzed by
cytochrome P450s, is probably responsible for the clearance of>75% of the
drugs on the market (Williams et al., 2004). Activities of CYPs are affected by
numerous factors like genetics, age, sex, disease, inhibitors, and inducers.
Genetic polymorphisms affect the activity of a number of drug-metabolizing
enzymes such as CYP2C19, CYP2D6, CYP1A2. For example, genetic
polymorphism in the CYP2D6, which is found in 5–10% of Caucasians, gives
rise to poor metabolizers that have low or lack of activity (Parkinson, 2001).
Therefore, for drugs metabolized by CYP2D6, dose adjustment may be needed
in patients that are poor metabolizers. Similarly, age, sex, and disease state
could also have an effect on the activity of the drug–metabolizing enzyme.
Thus, during drug development, where appropriate, subjects that show genetic
polymorphisms toward the enzyme(s) that is involved in the drugs metabolism
(e.g., CYP2D6 poor metabolizer), subjects of different age (old and young),
both sexes, and special populations (e.g., hepatically impaired) are included in
the clinical trial process to understand the pharmacokinetic variability. The
results from these studies are included in the label to help prescribing
physicians adjust the dose or, if necessary, avoid giving the drug to patients.
The other two factors that have an effect on the disposition of a drug are
coadministered medicines that are inhibitors or inducers of drug metabolism
enzymes. These types of drug–drug interactions are increasingly being observed
and have resulted in the withdrawal of numerous drugs from the market or
have restricted their use (Huang and Lesko, 2004). Because of the implication
that these types of interactions have toward safety and efficacy, the FDA and
European regulatory agencies have provided guidelines to address them during
the drug development process (Products; US Food and Drug Administration).
Understanding the ADME properties of the drug helps to address some of the
drug–drug interaction potential for a drug (Kumar and Surapaneni, 2001).
9.1.2 Drug Metabolism and Issue Resolution
Issue-driven metabolism studies, conducted when either animal toxicity or
clinical safety findings are observed, are an important part of the drug
development process. These studies help to define the role of drug and drug-
derived metabolites in the observed toxicity or safety findings. Although issues
regarding clinical safety or toxicity findings in animals are frequent in drug
262 ROLE OF DRUG METABOLISM IN DRUG DEVELOPMENT