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274 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
Nitro groups can be reduced to primary amines in a series of steps that involve an initial reduction
to a nitroso group, followed by a second reduction to a hydroxylamine, and finally end with a third
reduction to a primary amine. Please note that the reduction of the nitroso group to a primary amine
is the reverse of what was previously discussed for the oxidation of primary amines. Also note that
while oxidation adds ox ygen atoms to atoms and functional groups, reduction of a nitro group removes
oxygen atoms and adds hydrogen. An example of this stepwise reduction is shown in Figure 8-30
with nitrofurantoin. Examples of other drugs capable of this metabolic transformation are also
shown in the figure.
FIGURE 8-30.The reduction of the nitro group of nitrofurantoin by nitroreductase
enzymes and examples of other drug molecules that contain a nitro functional group
(see boxes).
Miscellaneous Reductions
Drug molecules that contain disulfide bonds as part of their structure can be reduced to thiol (or
sulfhydryl) metabolites. The general reaction is shown below. Examples include insulin and eptifibatide. Insulin is an endogenous peptide that contains three disulfide bonds. Two of these are
interstrand disulfide bonds that hold the A and B chains together, and the other one is an intrastrand
disulfide bond that is necessary for the proper conformation of the two chains. Eptifibatide is a cyclical peptide used to treat acute coronary syndromes. The cyclical nature is due to the presence of a
disulfide bond. Similar to azo and nitro groups, not many drug molecules contain disulfide bonds as
part of their structure.
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Sulfoxides are normally oxidized to sulfones, as shown in Figure 8-25; however, there are some
instances in which they are instead reduced to sulfides. One such instance is seen with the nonsteroidal anti-inflammatory drug (NSAID) sulindac (Figure 8-31). Sulindac is a prodrug. Reduction
of its sulfoxide functional group to a sulfide is required for its pharmacological actions.
FIGURE 8-31.The reduction of the sulfoxide group of sulindac.
PHASE I METABOLISM: HYDROLYSIS
Taken literally, the term hydrolysis means “water” (hydro) to “break” (lysis) a bond. Hydrolysis
involves the addition of a molecule of water across a C—X bond and the subsequent cleavage of that
bond. In most cases, X is an oxygen or nitrogen atom, and for some functional groups, the carbon
atom is replaced by a sulfur or phosphorous atom. Hydrolysis readily occurs with esters, amides, and
their cyclic analogs, lactones and lactams.
Hydrolysis is a common Phase I metabolic transformation because esters, amides, lactones, and
lactams are present in a significant number of drug molecules. The hydrolysis of these functional
groups leads to the formation of carboxylic acids, phenols, hydroxyl groups, and amines. All of these
metabolites are much more water soluble than the original drug molecule. The hydrolytic mechanism is illustrated below using the ester bond of aspirin.
Please note that this general mechanism is somewhat simplistic and does not indicate the fact
that esterase and amidase enzymes require specific amino acids for enzymatic catalysis. The amino
acids serine, threonine, tyrosine, histidine, aspartic acid, and glutamic acid are often involved in
enzymatic hydrolysis. Although not shown in the mechanism above, these amino acids are often
required to activate the water molecule and enhance its nucleophilicity. Additional examples of drug
molecules that undergo hydrolytic metabolism are shown in Figure 8-32. The hydrolysis of esmolol,
lidocaine, and cephalexin produces inactive metabolites whereas the hydrolysis of simvastatin converts this prodrug to its active metabolite.
Hydrolytic enzymes are ubiquitous in the human body. They are present in the liver but are also
widely distributed in other organs and tissues such as the GI tract, plasma, skin, lungs, and kidneys.
The lack of the need for hepatic metabolism has led to the development of locally active prodrugs.
276 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
FIGURE 8-32.Examples of ester, amide, lactone, and lactam hydrolysis (see boxes).
As discussed in Chapter 5, lipid-soluble ester prodrugs of glucocorticoids have been developed for
topical and pulmonary use. They are hydrolyzed at the site of application and generally do not enter
the systemic circulation to any significant extent, nor are they dependent on the liver for activation. Other drug molecules are administered as lipid-soluble esters to enhance their oral absorption.
After absorption, these ester prodrugs are hydrolyzed to their active metabolites. This concept was
introduced in Chapter 5 and used fenofibrate and candesartan cilexetil as examples. Four additional
examples are shown in Figure 8-33.
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FIGURE 8-33.Examples of ester prodrugs activated by hydrolysis (see boxes).
In some instances, hydrolysis can be mistakenly identified as oxidative O-dealkylation. This
error most commonly occurs when an ester is hydrolyzed and the carboxylic acid remains on the
drug metabolite. An example of this is illustrated in Figure 8-34 with a closer look at the hydrolysis
of diphenoxylate (originally shown in Figure 8-33). The active metabolite of diphenoxylate requires
the removal of the ethyl group and the formation of a carboxylic acid. As shown in Figure 8-34, this
FIGURE 8-34.Comparison of hydrolysis and oxidative
O
-dealkylation.
278 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
could theoretically occur by either hydrolysis or oxidative O-dealkylation. Regardless of the metabolic pathway, the same active metabolite is formed; however, there is a difference in the resulting
two-carbon unit. Hydrolysis produces a primary hydroxyl group whereas oxidative O-dealkylation
produces an aldehyde. These small two-carbon metabolites are often not shown in a metabolic
scheme, so how are we able to correctly conclude which metabolic pathway occurred?
This can be accomplished by comparing the mechanisms of metabolic transformation for
these two processes. Oxidative O-dealkylation requires CYP450 enzymes, the presence of a hydrogen atom that can be abstracted, and an eight-step metabolic process. In contrast, hydrolysis is a
much simpler process requiring two or three steps. Although both CYP450 enzymes and hydrolytic
enzymes exist in the liver, the overall distribution and availability of these enzymes is much greater
for hydrolytic enzymes. As previously discussed, metabolic processes within the human body are
extremely efficient and will not use a more complicated pathway when a simpler and more available pathway is present. In conclusion, whenever there is a choice between hydrolysis and oxidative
O-dealkylation, hydrolysis occurs, not oxidative O-dealkylation.
Steric hindrance can determine the site and rate of hydrolysis. Easily accessible esters and
amides are hydrolyzed to a greater extent than those located in the middle of the molecule and/
or are surrounded by other functional groups. A classic example of this is seen with cocaine. It contains an easily accessible methyl ester as well as a more sterically hindered benzylic ester. While
studies show that the hydrolysis of both esters occurs, the hydrolysis of the methyl ester is a major
metabolic pathway and the hydrolysis of the benzylic ester is a minor metabolic pathway. An additional example is provided in Figure 8-32 with simvastatin. The lactone is easily accessible, lacks any
significant steric hindrance, and is easily hydrolyzed. In contrast, the 2,2-dimethylbutyl ester is less
accessible and is somewhat sterically hindered. Although it can be hydrolyzed, the overall rate and
extent is less than that of the lactone.
In general, amides and lactams are hydrolyzed at a slower rate than are esters and lactones. A
classic example is seen in the comparison of procaine with procainamide. As shown in the structures
below, the only chemical difference between these two drugs is that procaine contains an ester and
procainamide contains an amide. Due to rapid ester hydrolysis, procaine has a half-life less than
one minute. As such, it cannot be administered orally and is used parenterally as a local anesthetic.
In contrast, the amide ester of procainamide is hydrolyzed at a much slower rate; in fact, hydrolysis
is not the primary metabolic route for procainamide. Procainamide can be given orally for the treatment of certain types of arrhythmias.
This is not to say that amides and lactams cannot be rapidly hydrolyzed because there are
several examples of this occurring. The amide bond of lidocaine (Figure 8-32) is rapidly hydrolyzed,
and its duration of action when given intravenously is only 10 to 20 minutes. The β-lactam class of
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antibiotics, exemplified by cephalexin in Figure 8-32, is subject to rapid lactam hydrolysis in basic
environments. Additionally, some β-lactams can be rapidly hydrolyzed by the bacterial enzyme
β-lactamase. Finally, proteins and peptides can be rapidly destroyed in the GI tract, the plasma, the
liver, and other cells by exopeptidases and endopeptidases that break specific peptide (i.e., amide)
bonds present within the protein or peptide.
A number of other functional groups can be metabolized via hydrolytic cleavage. These functional groups are not as prevalent in drug molecules and include phosphate esters, sulfonylureas,
carbamates, and glycosides. Examples of each of these are shown in Figure 8-35. Please note that
hydrolysis is a very minor metabolic pathway for some of these functional groups, especially sulfonylureas and carbamates.
FIGURE 8-35.Examples of other functional groups that can be metabolized by hydrolysis
(see boxes).
The hydrolysis of Phase II metabolites is known as deconjugation and serves two important
roles. First, deconjugation may help to extend the duration of action of a drug molecule. Some glucuronide conjugates are secreted into the small intestine for fecal elimination; however, due to the
presence of β-glucuronidases in the intestine, these conjugates can be hydrolyzed and the deconjugated drug molecule can then be reabsorbed. This process is known as enterohepatic recycling and
allows the drug to reside within the body for a longer period. Second, sulfate conjugates can be used
by the body to transport lipid-soluble drugs and biomolecules from one tissue to another. A good
example is seen with estrogens. Organ- and tissue-specific sulfatase enzymes serve to liberate the
active drug molecules at their site of pharmacological action. Examples of each of these deconjugation pathways are shown in Figure 8-36.
280 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
FIGURE 8-36.Examples of Phase II metabolites that can be deconjugated by hydrolysis.
Summary of Phase I Metabolism
• Phase I metabolism uses oxidation, reduction, and hydrolysis to add, alter, or unmask
specific functional groups. The minimum number of metabolic transformations
required to achieve these goals will occur.
• Functional groups that are easily accessible and not hindered by steric or electronic
factors are the most likely to undergo Phase I metabolism.
• Phase I metabolism increases the water solubility of a drug molecule. In some
instances, this is sufficient to allow the drug molecule to be eliminated from the body.
In other instances, Phase II metabolism is required.
• There is no specific requirement for a drug molecule to undergo Phase I metabolism.
Drug molecules that have sufficient water solubility are often excreted unchanged.
Drug molecules that already contain functional groups that can directly undergo
Phase II conjugation may bypass Phase I metabolism.
• Phase I metabolism may convert an inactive prodrug to an active metabolite.
• Phase I metabolism may convert an active drug molecule into a metabolite that
retains similar pharmacological activity.
• Phase I metabolism may convert a drug molecule into a metabolite that has increased
toxicity or is responsible for specific side effects.
• Phase I metabolism may convert an active drug molecule into an inactive and nontoxic
metabolite.
PHASE II METABOLISM: CONJUGATION
Six Phase II conjugation pathways are available for drug molecules: (1) glucuronic acid conjugation,
(2) sulfate conjugation, (3) amino acid conjugation, (4) glutathione conjugation, (5) acetylation, and
(6) methylation. Each conjugation pathway uses a specific transferase enzyme that catalyzes the
addition of one of these endogenous substances to a functional group that was initially present on a
drug molecule or was added or unmasked during one or more Phase I transformations. Conjugation of
a functional group with glucuronic acid, sulfate, or an amino acid (e.g., glycine or glutamine) greatly
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enhances the water solubility and excretion of a drug molecule. The products of these conjugations
are usually inactive; however, there are some instances in which glucuronide and sulfate conjugates
retain pharmacological activity. Glutathione reacts with highly electrophilic intermediates and thus
serves to detoxify drug molecules and toxic substances. Glutathione conjugates are highly water
soluble, readily excreted, and nontoxic. The addition of methyl or acetyl groups does not enhance
water solubility but often serves to terminate the pharmacological actions of the drug molecule.
Glutathione conjugation is different from the other five conjugation pathways in two respects.
First, all other Phase II conjugation pathways require an initial activation process that enhances the
reactivity of the conjugating group, the transferase enzyme, or a specific functional group present
on the drug molecule. These activated intermediates serve as cofactors for the transferase enzymes.
This initial activation is not necessary for glutathione conjugation because its nucleophilic sulfhydryl group can easily react with a potentially harmful electrophilic functional group. Additionally,
because the role of glutathione is to protect cells and tissues from highly reactive electrophiles,
it needs to be able to act immediately, without the requirement of an activation process. Second,
deconjugating enzymes can reverse the actions of all other Phase II conjugations. As mentioned
above, this process is important for the enterohepatic recycling and transport of specific drugs.
Because glutathione conjugation protects cells and tissues from potentially harmful electrophilic
substances or functional groups, there is no beneficial reason to reverse this process and regenerate
toxic substances once they are neutralized.
Table 8-2 provides a list of all six conjugation pathways, the endogenous substance used for
conjugation, the names of the activated cofactors, the names of the transferase enzymes used for
conjugation, and the names of the deconjugating enzymes.
TABLE 8-2.Summary of Phase II Conjugation Pathways
Conjugation
Pathway
Glucuronic acid
conjugation
Sulfate
conjugation
Amino acid
conjugation
Glutathione
conjugation
Acetylation Acetyl CoA Acetylated
Methylation Methionine S-Adenosylmethionine
Endogenous
Substance Activated Cofactor Transferase Enzyme
Glucose-1-phosphate UDP-glucuronic acid
Sulfate 3′-Phosphoadenosine-
Glycine and
glutamine (major)
Aspartic acid, serine,
and taurine (minor)
Glutathione (GSH) None Glutathione
(UDPGA)
5′-phosphosulfate
(PAPS)
Acyl coenzyme A
intermediate of
carboxylic acid on
the drug molecule
N-acetyltransferase
(SAM)
UDP-Glucuronyl-
transferase (UGT)
Sulfotransferase
(SULT)
N-Acyltransferase
(NAT)
S-transferase
N-Acetyltransferase Amidase
Methyltransferase CYP450 (i.e.,
Deconjugating
Enzyme
b-Glucuronidase
Sulfatase
Amidase
None
oxidative
dealkylation)
Glucuronic Acid Conjugation
Glucuronic acid conjugation is the most common Phase II transformation pathway for two reasons.
First, glucuronic acid is readily available because it is an oxidative metabolite of glucose. Second,
there are many functional groups that can be conjugated with glucuronic acid, including hydroxyl
groups, phenols, carboxylic acids, tetrazoles, amines, sulfonamides, hydrazines, carbamates, and
282 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
sulfhydryl groups. Phenols and hydroxyl groups are the two most common functional groups that
undergo glucuronide conjugation. Due to steric hindrance, tertiary hydroxyl groups and tertiary
amines are less likely to undergo glucuronic acid conjugation compared with the other functional
groups.
The mechanism of glucuronic acid conjugation involves three steps (Figure 8-37). The first two
steps convert glucose 1-phosphate to UDP-glucuronic acid (UDPGA). The third step is catalyzed by
UDP-glucuronyltransferase (UGT) and transfers the activated glucuronic acid to its target functional
group. There are two human UGT subfamilies, UGT1 and UGT2, and a large number of isoforms.
Each isoform is responsible for the glucuronidation of specific functional groups; however, there is
considerable overlap among the isoforms.
FIGURE 8-37.The mechanism of glucuronide conjugation.
A number of cells are capable of converting glucose 1-phosphate to UDP-glucose because this
step is also required for the formation of glycogen. A key point in this initial step is that the α anomer of glucose 1-phosphate is required. Subsequent oxidation of UDP-glucose yields UDP-glucuronic
acid. In the conjugation step, a functional group on the drug molecule displaces UDP. This displacement occurs from the opposite side of the UDP molecule. Because this sequence always begins with
the α anomer of glucose 1-phosphate, the conjugation product is always a b-glucuronide.
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Examples of drug molecules capable of undergoing glucuronide conjugation are shown in
Figure 8-38. Each drug molecule has been chosen to represent a specific functional group that is
capable of undergoing this conjugation pathway.
FIGURE 8-38.Examples of drug molecules that can undergo glucuronide conjugation
(susceptible functional groups are boxed).
The addition of glucuronic acid to a drug molecule greatly enhances its water solubility due to
the negatively charged carboxylic acid and the three secondary hydroxyl groups, all of which are
hydrophilic in character. This is shown in Figure 8-39 with the glucuronide conjugates of acetaminophen and atomoxetine. Please note that the stereochemistry of these metabolites matches the
stereochemistry shown in the mechanism of glucuronide conjugation in Figure 8-37.
Some drugs may possess more than one functional group that can undergo glucuronide conjugation. In these situations, multiple glucuronide metabolites may be formed; however, it is uncommon
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