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Review of Drug Metabolism in Drug
Discovery and Development
RONALD E. WHITE
White Global Pharma Consultants, LLC, Cranbury, NJ, USA
1.1
1.2
1.3
1.4
1.5
1.6
1.7
1.8
Summary
Introduction
The phenomenon of drug metabolism
The drug discovery and development process
The significance and importance of drug metabolism
The biochemical process of drug metabolism
The chemical characterization of drug metabolism
Conclusion
Abbreviations
References
1
2
3
12
14
19
30
33
34
34
1.1
SUMMARY
Drug metabolism is a physiological phenomenon in which xenobiotic compounds
are chemically transformed into metabolites of the parent drug. Drug metabolism
comprises a diverse set of chemical reactions within four general categories: oxidation,
reduction, conjugation, and hydrolysis. These general categories of chemical reactions
correspond to general categories of enzymes, which are responsible for catalyzing the
reactions. The object of drug metabolism is to clear the xenobiotics from the body, so
that the metabolites tend to be more polar and soluble than the parent drug, making
them easier to excrete. Transporters are now recognized as a necessary component of
drug metabolism, since they facilitate penetration of the parent drug into metabolizing
organs and passage of ionic metabolites across cell membranes into the excreta. Drug
metabolism is important in the clinical action of drugs because it is often the main
means by which drugs are cleared from the body, so the rate of metabolism is one deter-
minant of the elimination half-life of the drug. Drug metabolism is additionally impor-
tant because the metabolites may have pharmacological or toxicological properties,
which are superimposed on the clinical profile of the parent drug. For these reasons, the
drug discovery process aims to design molecules with rates of metabolism appropriate
for clinical use and pathways of metabolism which minimize side effects or toxicities
attributable to metabolites. In clinical development, characterization of the metabolic
Encyclopedia of Drug Metabolism and Interactions, 6-Volume Set,
First Edition.
Edited by Alexander V. Lyubimov.
©
2012 John Wiley & Sons, Inc. Published 2012 by John Wiley & Sons, Inc.
1
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REVIEW OF DRUG METABOLISM IN DRUG DISCOVERY AND DEVELOPMENT
pathways, the major circulating metabolites, and the enzymes that produce these
metabolites is necessary for a full understanding of the clinical profile of a new drug.
Accordingly, several types of clinical studies of metabolism are mandated for new drug
registration, including identification and quantitation of major circulating metabolites,
determination of the major pathways of clearance (CL) and their associated metabolic
enzymes, characterization of drug–drug interactions based on metabolic phenomena,
and assessment of the extent of excretion of drug-derived materials from the body.
1.2
INTRODUCTION
When an organic compound enters the human body, it is normally (i) utilized as a
nutrient, (ii) directly excreted, or (iii) chemically modified and then excreted. In the
case of a nutrient, the molecules enter specific biochemical pathways that either split
them into small units followed by complete oxidation to generate energy (catabolism)
or utilize them as precursors for constructing physiological molecules such as nucleic
acids, polysaccharides, proteins, and triglycerides (anabolism). The overall process of
utilization of nutrients is called
intermediary metabolism.
An example is the splitting
of dietary fatty acids such as palmitic acid into two-carbon acetyl CoA units that can
be oxidized in the mitochondria to produce energy (as ATP).
CH
3
−(CH
2
)
14
−COOH →
8CH
3
CO−SCoA
→
16CO
2
+
12H
2
O
(+107ATP)
In cases of nonnutrient compounds (xenobiotics), however, pathways for signif-
icant energy production seldom exist, although in some cases the body is able to
partially metabolize an organic compound for its energy content, as for instance with
N-demethylation of drugs (Section 1.3).
R−NMe
2
+
NADPH
+
O
2
→
R−NHMe
+
HCHO
→
HCOOH
+
NADH
→
CO
2
+
NADH
(equivalent
to 3ATPs)
The methyl group is released as formaldehyde, which is further oxidized to for-
mate and finally carbon dioxide, generating 2 mol of NADH. However, since 1 mol
of NADPH must be invested for the metabolic demethylation, then the net energy
production is 1 mol of NADH, equivalent to 3 mols of ATP. Most such reactions of
xenobiotics are either energy-neutral (e.g., hydrolyses) or actually energy-consumptive
(e.g., hydroxylations), since they produce no energy equivalents, but may use cofactors
such as NADPH, PAPS, SAM (S-adenosine-L-methionine), or UDPGA, which require
cellular ATP equivalents for their synthesis.
With the majority of xenobiotics, only a limited set of nonspecific chemical modi-
fications is possible. This process is called
drug metabolism,
although it occurs with
all absorbed foreign compounds, and not just drugs. To avoid confusion with interme-
diary metabolism, drug metabolism is sometimes called
biotransformation.
However,
in fact, there is rarely any serious confusion between these two terms, and the term
biotransformation
is not really descriptive enough to convey a clear meaning in any
event. So, most scientists working in this field simply call it
drug metabolism.
For
the purposes of this chapter, we make no distinction between xenobiotic chemical
THE PHENOMENON OF DRUG METABOLISM
3
compounds that are unintentionally introduced into the body (e.g., natural plant alka-
loids or environmental chemicals) and those that are intentionally dosed (e.g., medicinal
drugs). The same CL mechanisms operate on all xenobiotics, and we use the term
drug
metabolism
to describe the chemical modification of any nonphysiological compound.
Drug metabolism occurs in all species, from bacteria to humans, but our primary focus
in this chapter is the human phenomenon, only with reference to other species, as they
are relevant to the process of discovery and development of new drugs. An increas-
ing proportion of new drugs are proteins and nucleic acids (i.e.,
biologics),
but the
scope of this chapter is limited to the discussion of traditional small-molecule organic
compounds.
The recognition that foreign substances may be metabolized in the body goes back
almost two centuries, and an interesting history of the early discoveries is available
in the form of a journal article [1] or website [2]. About 60 years ago, biochemists
began to recognize drug metabolism as a distinct field of study. Soon, scientists in
academia, pharmaceutical companies, and regulatory agencies realized that character-
ization of the metabolic fate of drugs was an important component in understanding
their clinical profiles. Initially, it was sufficient to merely demonstrate that a dosed
drug and/or its metabolites were eliminated from the body in a reasonable amount of
time. Next, in the evolution of drug metabolism, there was a need to determine the
chemical form of the major drug-related materials in the excreta. Today, the potential
role of circulating metabolites in therapeutic action as well as toxicity has become
apparent, and a sophisticated quantitative chemical, biochemical, pharmacological,
and toxicological description of metabolism is required for the registration of new
drugs.
Finally, we can ask “What is the object of drug metabolism?” As can be seen in
subsequent sections, drug metabolism is more than just an attempt by the body to “eat”
ingested foreign compounds. The existence of a complex, regulated, and interacting set
of barriers and CL mechanisms suggests that the object is to chemically and physically
limit the entry of these compounds to the body and facilitate their removal from the
body. Those compounds that are not clearable by direct excretion in urine or feces are
subject to sequential rounds of metabolism, which change their chemical and physical
properties until they
can
be excreted. With these thoughts in mind, let us discuss in
detail exactly what drug metabolism is and why it is important to the discovery and
development of new drugs.
1.3
THE PHENOMENON OF DRUG METABOLISM
Drug metabolism comprises such a rich variety of chemical modifications of organic
compounds that it is rare to find a drug that is not subject to some type of metabolic
process. Of course, there is a kinetic component of the drug-metabolism process as
well, so in some cases the metabolism occurs only slowly. For example, amiodarone
is cleared from the body exclusively by metabolism [3], but because the metabolic
process is very slow, this drug has a 55-day terminal half-life [4]. In other cases, the
direct excretion process is much faster than metabolism and dominates CL. So we find
that amoxicillin, for example, is mainly excreted as the intact parent drug in urine [5].
Nonetheless, most drugs are rapidly metabolized as the major route of CL from the
body. Although the diverse manifold of possible reactions presents a complex array of
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REVIEW OF DRUG METABOLISM IN DRUG DISCOVERY AND DEVELOPMENT
possibilities, we can recognize some patterns, so that it is possible to use relatively few
terms to describe virtually all the transformations. In fact, there are only four major
categories: oxidations, reductions, conjugations, and hydrolyses.
These four categories of chemical transformation arise from four broad classes
of enzymes, which actually accomplish the transformation for a particular drug. It is
common, if not universal, for a particular drug to be subject to more than one metabolic
conversion. For example, dextromethorphan has two major metabolites, one resulting
from N-demethylation and the other from O-demethylation (Fig. 1.1).
As one would expect, some metabolites are the product of sequential operation of
two or more of these basic transformations, as shown for loratadine, which under-
goes oxidative decarboethoxylation followed by aromatic hydroxylation and finally
glucuronidation (Fig. 1.2).
Occasionally, a metabolic pathway apparently not conforming to this fourfold cat-
egorization is encountered, as shown in Fig. 1.3.
However, almost always, closer examination shows that the process was actually a
diversion during operation of one of the four standard categories [8,9]. In the example
in Fig. 1.3, pulegone is first hydroxylated on an allylic methyl group, followed by
internal hemiketal formation and dehydrative aromatization to form menthofuran [10].
H
3
C
O
H
3
C
O
+
HO
N
CH
3
NH
N
CH
3
Figure 1.1
N- and O-demethylation of dextromethorphan [6].
Cl
N
N
Cl
N
CO
2
Et
N
H
HOOC
HO
HO
O
OH
O
N
Cl
HO
N
Cl
N
H
N
H
Figure 1.2
Metabolic pathway for loratadine [7].
THE PHENOMENON OF DRUG METABOLISM
O
O
5
Figure 1.3
Ring closure of pulegone to menthofuran.
H
3
CO
N
F
3
C
CH
3
CH
3
F
3
C
N
H
3
C
N
N
O
CH
3
H
3
CO
N
CH
3
CH
3
N
H
3
C
O
CH
3
N N
OH
N
N
Figure 1.4
Ring contraction of vicriviroc [11].
A more vexing example is provided below by the contraction of a six-membered
pyrimidine ring to a five-membered pyrazole ring in the anti-HIV drug vicriviroc
(Fig. 1.4). Although no explanation for this reaction had been published, one can
write a plausible, albeit complex, metabolic pathway linking the parent drug and the
metabolite utilizing only known reactions from the four standard categories (details
left as an exercise for the reader).
Although many interesting chemical transformations are known in biochemistry, we
limit our discussion here only to ones that have been demonstrated to occur with xeno-
biotics. Table 1.1 summarizes the main chemical reactions of human drug metabolism.
Each metabolic reaction has been given a name descriptive of the overall chemical
transformation that occurs, regardless of the internal mechanism by which the trans-
formation was accomplished. However, in many cases, the metabolic reaction has a
name commonly used in the published literature of drug metabolism. For example,
“introduction of an oxygen atom at an aliphatic position” would typically be referred
to as
Hydroxylation,
even though an oxygen atom, not a hydroxyl group was added
to the molecule. The common name is given in parenthesis. Note that the drugs and
metabolites are drawn in their unionized forms to better see the chemical transforma-
tion that has occurred. Although Table 1.1 is intended to be reasonably comprehensive
for introductory purposes, it is not exhaustive. A number of unusual examples have
been compiled elsewhere [8,9].
Finally, it is worth noting that some metabolic reactions can be reversed, leading
to the phenomenon of
futile cycling.
A metabolite that is produced through one of the
metabolic reactions in Table 1.1 may be reconverted to the parent drug by another
metabolic reaction, with no net chemical transformation. An example is the conver-
sion of a tertiary amine to an
N-oxide
(Reaction I.F). Since some
N-oxides
can be
reduced to tertiary amines (Reaction II.B), the result is that the amine appears not to
have been metabolized, when in fact two metabolic steps occurred [32]. The existence

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