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284 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
FIGURE 8-39.Glucuronide conjugates of acetaminophen and atomoxetine
that any single metabolite would be conjugated with more than one glucuronic acid. Once adequate
water solubility has been added to a drug molecule to ensure its elimination from the body, there
simply is no need to metabolize the drug molecule any further. Glucuronide conjugates are easily
excreted in the urine. Although most glucuronide conjugates are inactive, there are instances in
which activity is retained or enhanced by this conjugation. Morphine and dabigatran provide two
examples in which their glucuronide conjugates retain activity or have enhanced activity as compared with the parent drug. The C6 glucuronide conjugate of morphine is two to three times more
active than morphine whereas the glucuronide conjugate of dabigatran retains the same activity as
the unconjugated drug. Interestingly, glucuronide conjugation of morphine can produce either inactive or more active metabolites depending on the site of metabolism. Glucuronide conjugation at
the C6 hydroxyl group produces a more active metabolite whereas glucuronide conjugation at the C3
hydroxyl group (Figure 8-36) produces an inactive metabolite.
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As previously mentioned, some glucuronide conjugates are excreted in the bile and subsequently
deconjugated in the GI tract by the enzyme β-glucuronidase. The resulting drugs, metabolites, or
endogenous substances can then be reabsorbed via a process known as enterohepatic circulation
or enterohepatic recycling. In general, drug molecules with a molecular weight more than 500 are
more likely to undergo this process than those with a lower molecular weight. Oral contraceptives,
thyroid hormones, raloxifene (shown in Figure 8-40), indomethacin, morphine, pentazocine, and
diazepam are examples of drug molecules for which enterohepatic recycling is important to their
metabolism, elimination, and duration of action.
FIGURE 8-40.Enterohepatic circulation of raloxifene.
Sulfate Conjugation
Sulfate conjugation occurs primarily with phenolic hydroxyl groups; however, it can also occur to a
minor extent with aliphatic hydroxyl groups, aromatic amines, and N-hydroxyl groups. Unlike glucuronic acid, which is readily synthesized from glucose, the body has a much more limited pool of sulfate. Depending on the dose of the drug, it is possible that this pool of sulfate can become depleted,
and other metabolic pathways may need to be used. In many cases, when a functional group or
drug molecule can be conjugated with either glucuronic acid or sulfate, glucuronide conjugation
predominates. Examples of this are seen with both acetaminophen and sulfisoxazole. Although the
phenolic hydroxyl group of acetaminophen and the aromatic amine of sulfisoxazole can undergo
sulfate conjugation, these are minor metabolic products compared with glucuronide conjugation
pathways indicated in Figure 8-38.
The mechanism of sulfate conjugation is shown in Figure 8-41. Similar to glucuronide conjugation, the first two s teps convert inorganic sulfate to an activated intermediate, 3′-phosphoadenosine-
5′-phosphosulfate (PAPS). In the third step, the enzyme sulfotransferase (SULT) catalyzes the
transfer of the activated sulfate to its target functional group. There are two human sulfotransferase
families, SULT1 and SULT2, and numerous subfamilies and isoforms. Similar to UGT isoforms, each
SULT isoform is responsible for the transfer of sulfate to specific functional groups.
Examples of sulfate conjugation are shown in Figure 8-42. Given that phenols are the primary
substrates for sulfate conjugation, the addition of an ionized sulfate group greatly enhances the
water solubility of these drugs and enhances their excretion. As previously mentioned, sulfate conjugation of estrogens increases their ability to be transported in the plasma to target cells and tissues. These target cells contain the enzyme sulfatase that removes the sulfate group and allows for
essential estrogen activity. While most sulfated conjugates are pharmacologically inactive, there are
a few rare examples in which sulfate conjugation produces an active metabolite. One such example
286 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
FIGURE 8-41.The mechanism of sulfate conjugation.
is seen with minoxidil. Minoxidil is an antihypertensive agent; however, it does not produce its beneficial therapeutic effects until it is sulfated. Interestingly, conjugation of minoxidil to its glucuronic
acid metabolite produces an inactive drug.
Sulfate conjugation can also lead to the production of highly reactive and cytotoxic intermediates. This can occur with aromatic amines that have been oxidized to hydroxylamines via Phase I
metabolism, as illustrated in Figure 8-43. Sulfate conjugation of these hydroxylamines can lead to
a subsequent reaction in which the sulfate is eliminated and an electrophilic intermediate capable
of reacting with proteins, enzymes, and/or DNA is formed. This mechanism has been proposed to
be responsible for the carcinogenic effects of some polycyclic aromatic amines. Fortunately, this
sequence of reactions is a minor metabolic pathway for drug molecules, and depending on the dose
of the drug, glutathione can potentially completely neutralize these toxic metabolites.
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FIGURE 8-42.Examples of sulfate conjugation.
FIGURE 8-43.The formation of electrophilic intermediates from sulfate conjugates.
288 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
Amino Acid Conjugation
This conjugation pathway adds amino acids to carboxylic acids that are either initially present within
the structure of a drug molecule or introduced by Phase I metabolism. The two most commonly used
amino acids in this conjugation process are glycine and glutamine. Aspartic acid, serine, and taurine
(H2NCH2CH2SO3H) are also used to a minor extent. Because excess amino acids are not stored in
the human body, only a limited supply is available for conjugation. Glucuronic acid conjugation often
competes with amino acid conjugation, so amino acid conjugation is primarily limited to aromatic carboxylic acids and aryl acetic carboxylic acids. The presence of an adjacent α-carbon on an aryl acetic
carboxylic acid tends to s terically hind er amino acid conjugation and favor glucuronic acid conjugation.
Similar to glucuronic acid and sulfate conjugation, there is an initial two-step activation
sequence that is required prior to the addition of an amino acid to a carboxylic acid. The main difference in this transformation is that the carboxylic acid present within the structure of the drug
molecule is activated instead of the amino acid. The mechanism of amino acid conjugation is shown
in Figure 8-44 using salicylic acid as an example. In the first step, the carboxylic acid reacts with
adenosine triphosphate (ATP) to form a reactive acid anhydride. In the second step, coenzyme A
displaces adenosine monophosphate (AMP) to form the activated acyl coenzyme A intermediate. It
FIGURE 8-44.The mechanism of amino acid conjugation.
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should be noted that the major function of coenzyme A in biochemical pathways is to activate and
transfer acyl groups. In the citric acid cycle and other biochemical pathways, it serves as the activated carrier of acetyl groups, a specific two-carbon acyl group. In this pathway, coenzyme A serves
as the activated carrier of acyl groups of drug molecules. The final conjugation step is catalyzed by
either glycine or glutamine N-acyltransferase.
When comparing the water solubility of salicylic acid to that of its glycine conjugate, both molecules contain a carboxylic acid; however, the amino acid conjugate provides additional hydrogen
binding due to the presence of the amide bond. When glutamine is the amino acid conjugate, it
has the ability to participate in additional hydrogen bonding interactions not possible with glycine.
Some additional examples of amino acid conjugation are seen in Figure 8-45. Rizatriptan provides
an example of a coupled Phase I and Phase II metabolic transformation. Initially, the tertiary amine
would need to undergo a minimum of three Phase I metabolic reactions: an N-dealkylation of one
FIGURE 8-45.Examples of amino acid conjugation.
290 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
of the methyl groups, oxidative deamination of remaining secondary amine, and oxidation of the
resulting aldehyde to a carboxylic acid. The resulting carboxylic acid could then undergo Phase II
amino acid conjugation to further enhance its water solubility and aid in its elimination. Amino acid
conjugation can be reversed, or deconjugated, by amidases; however, this is much less common than
the deconjugation reactions seen with glucuronic acid and sulfate conjugates.
Glutathione Conjugation
Glutathione is what has been called “the true detoxifying agent.” It is present in virtually all mammalian tissues and protects the body from potentially harmful electrophiles that are either initially
present within the structure of an endogenous or exogenous compound or arise as a product of
metabolic processes. Unlike all of the other conjugation pathways, glutathione can form conjugates
without the need for activation. In this manner it can promptly inactivate any potentially harmful
threats to cells and tissues. As previously mentioned, glutathione conjugation is the only conjugation pathway that cannot be reversed by a deconjugating enzyme.
Similar to glucuronic acid conjugation, glutathione can react with a large number of functional
groups. The main criterion is that the functional group must be sufficiently electrophilic. In terms of
general reaction mechanisms, functional groups susceptible to glutathione conjugation fall into two
main categories: those that undergo nucleophilic substitution at either a carbon atom or a heteroatom
and those that act as a Michael acceptor (e.g., double bond conjugated to a carbonyl), as shown below.
Glutathione is a tripeptide consisting of γ-glutamate, cysteine, and glycine. The general
mechanism of glutathione conjugation is shown in Figure 8-46. The sulfhydryl group of cysteine is
FIGURE 8-46.The mechanism of glutathione conjugation.
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nucleophilic and readily reacts with an electrophilic functional group present within a drug molecule
(designated as R—E). Because the reactivity is due to the sulfhydryl group, glutathione is commonly
abbreviated as GSH. The enzyme responsible for this initial reaction is glutathione S-transferase.
The resulting glutathione conjugate is generally inactive and nontoxic. This initial conjugate normally undergoes three additional reactions to form what is known as a mercapturic acid, or an
N-acetylcysteine conjugate. As shown in Figure 8-46, γ-glutamate and glycine are sequentially
removed, and the N-terminal amine of cysteine is acetylated. The remaining N-acetylcysteine conjugate provides adequate water solubility for elimination by virtue of its ionized carboxylic acid and
the hydrogen bonding ability of the amide. Although glutathione conjugation does not require activation and cannot be reversed by a deconjugating enzyme, it is the only conjugating pathway that
undergoes further metabolism after the initial conjugation has occurred.
Three examples of glutathione conjugation are shown in Figure 8-47. As previously discussed,
N-oxidation of approximately 1% to 2% of a normal dose of acetaminophen produces a highly
FIGURE 8-47.Examples of glutathione conjugation.
292 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
reactive electrophilic intermediate (Figure 8-20). Glutathione swiftly reacts with this intermediate
to produce an inactive and nontoxic metabolite. The second example uses the electrophilic intermediate that can be generated by sulfate conjugation of hydroxylamines (Figure 8-43). Once again,
glutathione can quickly react with this intermediate and remove any threat of toxicity. Finally, the
oxidation of aromatic hydrocarbons, such as benzo[a]pyrene, to epoxide intermediates produces
potential carcinogenic metabolites. Glutathione acts to detoxify these reactive intermediates.
As a final consideration, please note that while glutathione is readily available, the amount
present in any given cell or tissue is limited. Overdoses of acetaminophen and overexposure to carcinogenic compounds deplete glutathione stores, thereby allowing the electrophilic intermediates
to react with cellular nucleophiles, including proteins, enzymes, DNA, and other macromolecules.
Acetylation
This conjugation pathway uses acetyl CoA to acetylate drug molecules that contain primary aliphatic or aromatic amines, hydrazines, hydrazides, or unsubstituted sulfonamides. Although acetyl
CoA is readily abundant, acetylation is a relatively minor conjugation pathway because the required
functional groups are present only in a limited number of drug molecules. The most commonly
encountered functional group, a primary aliphatic amine, is normally metabolized by oxidative
deamination rather than acetylation. Unlike the previous four types of conjugation, acetylation does
not produce a more water-soluble metabolite. Acetylated metabolites tend to be more lipid soluble
than the original drug molecule and often must undergo additional metabolic transformations to be
sufficiently water soluble to be eliminated from the body.
The mechanism of acetylation is a two-step process as shown in Figure 8-48 using hydralazine as an example. In the first step, the acetyl group of acetyl CoA is transferred to the enzyme
N-acetyltransferase (NAT). In the second step, NAT transfers the acetyl group to the hydrazine
group of hydralazine. The transferase enzyme is regenerated in this process and is able to acetylate
additional drug molecules.
FIGURE 8-48.The mechanism of acetylation.
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Similar to other conjugation pathways, there are two major isoforms of N-acetyltransferase,
NAT1 and NAT2. Genetic polymorphism affects the rate of acetylation of drug molecules and can
affect their dosing and toxicity. The human population can be roughly divided into two groups: those
who are fast acetylators and those who are slow acetylators. Slow acetylators have a decreased
capacity to inactivate drug molecules for which acetylation is the primary metabolic route. Shown
in Figure 8-49 is the acetylation of procainamide, isoniazid, and sulfamethoxazole. This metabolic
pathway is the primary route of metabolism for these three drugs. Patients who are slow acetylators
are more prone to experience higher blood concentrations and potential toxicity with these drugs
than those who are fast acetylators. Conversely, fast acetylators may require higher doses or more
frequent administration of drug molecules that are metabolized by this route. In most instances,
acetylation produces an inactive metabolite; however, this is not always the case. The acetylation
of procainamide produces N-acetylprocainamide, an active antiarrhythmic drug. Acetylation can be
reversed through hydrolysis catalyzed by an amidase enzyme; however, this is not often observed.
FIGURE 8-49.Examples of drugs known to undergo acetylation as a major metabolic
pathway.
Similar to the coupled Phase I and Phase II metabolism of rizatriptan shown in Figure 8-45,
Figure 8-50 provides two additional examples of this concept. Neither tetracaine nor nimodipine
contains a functional group that can undergo acetylation; however, Phase I metabolic pathways
can provide a primary aromatic amine for both drugs. Tetracaine requires an initial N-dealkylation,
and nimodipine requires an initial reduction. Once these Phase I metabolic processes have occurred,
Phase II acetylation can provide the final product.
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