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294 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
FIGURE 8-50.Examples of coupled Phase I metabolism and Phase II acetylation.
Methylation
Methylation is extremely important in the biosynthesis of nucleic acids, proteins, phospholipids,
neurotransmitters, and other amines. In contrast, methylation is a minor metabolic pathway that
is seen only with catechols, phenolic hydroxyl groups, amines, and sulfhydryl groups. Each of these
functional groups is methylated by one of four different methyltransferase enzymes: catechol-
O-methyltransferase (COMT), phenol-O-methyltransferase (POMT), N-methyltransferase, or
S-methyltransferase. Drug molecules that contain a catechol ring (i.e., an aromatic ring with ortho
hydroxyl groups) are the most likely to undergo this Phase II conjugation. This includes endogenous amines, such as epinephrine and dopamine, as well as a number of adrenergic agonists, such
as methyldopa and isoproterenol. Due to the availability of other metabolic pathways, phenolic
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hydroxyl groups are only methylated to a minor extent. The methylation of amines is essential for
biosynthetic pathways, but of very limited importance as it relates to drug metabolism. As previously discussed, amines are primarily dealkylated and/or deaminated. Sulfhydryl groups can also
be methylated; however, due to their low prevalence in drug molecules, this is not often observed.
The methylation of functional groups occurs via a two-step process, shown in Figure 8-51.
The methyl donor is methionine; however, it must first be activated to transfer its methyl
group. The enzyme methionine adenosyl transferase uses methionine and ATP to synthesize
S-adenosylmethionine, commonly abbreviated as SAM. The positively charged sulfur atom is electrophilic and allows for the easy transfer of the methyl group to a catechol, a phenolic hydroxyl
group, an amine, or a sulfhydryl group. S-Adenosylhomocysteine can then be converted back to
methionine in two steps to allow additional methylations to occur.
FIGURE 8-51.The mechanism of methylation.
Examples of drugs that can undergo methylation are shown in Figure 8-52. Please note that the
methylation of catechols occurs preferentially at the meta position and that the N-methylation of
phenylpropanolamine is a minor metabolic pathway for this drug molecule. Similar to acetylation,
methylation does not enhance water solubility and does not enhance the elimination of drug molecules. Methylation instead often serves to inactivate drug molecules. Methylation can be reversed
through the process of oxidative dealkylation; however, this does not occur very often.
296 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
FIGURE 8-52.Examples of methylation.
The methylation of catechol rings serves a second purpose because it prevents their oxidation
to highly reactive intermediates, as shown below. As previously discussed, glutathione can help
neutralize or inactivate these types of reactive intermediates; however, without COMT, high doses
of catechol-containing drugs could deplete glutathione stores.
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Summary of Phase II Metabolism
• Phase II metabolism involves the conjugation of endogenous substances to functional
groups that were either initially present on the drug molecule or were introduced by
Phase I metabolic transformations.
• Conjugation with glucuronic acid, sulfate, or amino acids greatly enhances the water
solubility and, therefore, elimination of a drug molecule.
• Glutathione conjugation serves to neutralize or detoxify highly reactive electrophilic
intermediates.
• Acetylation and methylation do not enhance water solubility but usually act to ter-
minate the pharmacological actions of a drug molecule. These conjugates may require
additional metabolism to be water soluble enough for elimination.
• Although there are some exceptions, most Phase II conjugates are inactive and
nontoxic.
• Due to the readily available supply of glucuronic acid and the large number of func-
tional groups that are substrates for UGT, glucuronic acid conjugation is the most
common Phase II pathway.
• With the exception of glutathione conjugation, all other Phase II conjugations require
an initial activation of either the conjugating group, the transferase enzyme, or the
target functional group.
• With the exception of glutathione conjugation, all other Phase II conjugations can be
reversed by deconjugating enzymes.
Glucuronic acid conjugation and sulfate conjugation are the two most common
pathways to undergo a deconjugation step.
Through the process of enterohepatic cycling, deconjugation enzymes can help to
extend the duration of action of a drug molecule.
Deconjugation enzymes can liberate the active drug molecule at its site of pharmacological action.
Factors That Affect Drug Metabolism
Prior to summarizing the key concepts that govern metabolism, it should be noted that genetic differences, physiologic conditions, dosing regimen, dietary influences, and coadministration of other
drug molecules can affect the metabolic pathways that have been discussed in this chapter.
The field of study known as pharmacogenomics, or pharmacogenetics, seeks to evaluate
the effects of how an individual’s genes affect the response to medications. It is well known that
the genetic profile of an individual can alter the ability of that person to metabolize a given drug.
Individuals with specific genetic mutations, also known as genetic polymorphisms, may possess
metabolizing enzymes that are either less active or more active than those found in the general population. Additionally, certain patient populations have been shown to express different enzymatic
isoforms that are more or less active than the normal isoform (also known as the wild-type form).
This is mos t commonly seen with the cytochrome P450 monooxygenase enzymes, otherwise known
as CYP450 enzymes. Finally, genetic variations among patients or patient populations may alter the
number of copies of a given enzyme available for a specific type of metabolic transformation.
Three examples of known polymorphisms that affect metabolic pathways are discussed here.
The first example examines the metabolism of the S isomer of warfarin, the more active enantiomer.
This isomer is primarily metabolized by CYP2C9 to inactive 6- or 7-hydroxy metabolites, with the
7-hydroxywarfarin representing the major metabolite (Figure 8-53). More than 60 different alleles
have been identified for the CYP2C9 gene, with CYP2C9*2 and CYP2C9*3 being the most common.
298 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
FIGURE 8-53.Metabolism of warfarin by CYP2C9.
Patients who have the normal, or wild-type, CYP2C9 isozyme metabolize warfarin in a normal manner. In contrast, those who have the CYP2C9*2 and CYP2C9*3 alleles have impaired metabolism
and require lower doses to avoid adverse effects, specifically increased bleeding tendencies.
A second example is seen with clopidogrel. Clopidogrel is a prodrug that requires CYP2C19 oxidation of its thienopyridine ring to be converted to its active metabolite. This activation was discussed in Chapter 6 and can be found in Figure 6-7. Similar to CYP2C9, a large number of alleles have
been identified for CYP2C19. Individuals who possess specific variants of CYP2C19 are poor metabolizers of clopidogrel and fail to adequately convert the prodrug to its active form. Although routine
genetic testing for CYP2C19 polymorphisms in patients taking clopidogrel is not currently done,
there are published recommendations for poor and intermediate metabolizers for this isozyme.
The third and final example of polymorphisms and drug metabolism involves the metabolism of
metoprolol. While metoprolol can be oxidized by a number of CYP isozymes, its primary metabolizing enzyme is CYP2D6. As shown in Figure 8-54, metoprolol can undergo O-dealkylation (∼65%),
benzylic oxidation (∼10%), and N-dealkylation (∼10%). The O-dealkylated metabolite is rapidly further oxidized to an inactive carboxylic acid. Patients who are poor CYP2D6 metabolizers experience
several-fold higher concentrations of metoprolol compared with normal CYP2D6 metabolizers.
Although there are no current guidelines for the dosing of metoprolol based on a patient’s CYP2D6
status, numerous studies have shown that dosing reductions should be considered in patients who
are either intermediate CYP2D6 metabolizers or poor CYP2D6 metabolizers. Additionally, dosage
increases of metoprolol have been suggested for patients who are ultrarapid CYP2D6 metabolizers.
Age, existing disease states, and the nutritional status of a patient can also affect drug metabolism. In general, as an individual ages, his or her ability to metabolize drug molecules decreases.
Disease states that alter liver function have a pronounced effect on the metabolism of a number of
drugs. In these situations, specific dosing guidelines are listed in the drug product literature. Protein
and lipid deficiencies can also decrease drug metabolism.
The dose, route of administration, and frequency of administration also play a role in drug
metabolism. Let us look at a couple of general examples. Phase II conjugation pathways require
the addition of endogenous substances to the drug molecule. The liver, as well as any other
organ involved in this type of metabolism, has a finite amount of these endogenous substances
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FIGURE 8-54.Metabolism of metoprolol by CYP2D6.
(e.g., glucuronic acid, glutathione). As the dose or frequency of administration of a drug increases,
these pathways can become saturated and lead to alternative metabolic pathways. Additionally, the
liver often significantly metabolizes lipid-soluble drugs before they reach the systemic circulation.
This process, known as first-pass or presystemic metabolism, often significantly reduces the amount
of orally administered drug that is bioavailable. In some instances, this can be avoided by using a
different method of administration, such as a parenteral injection or a topical cream.
The coadministration of other drugs can affect drug metabolism in a number of ways. The most
common mechanism is through either the induction or inhibition of specific metabolizing enzymes.
Similar to the genetic deficiencies discussed above, this is most commonly seen with the CYP450
family of enzymes. Induction of CYP450 enzymes enhances their activity, increases the rate of drug
metabolism, and in mos t instances decreases the plasma level of the active drug molecule. Inhibition
of CYP450 enzymes decreases their activity, decreases the rate of drug metabolism, and in most
instances increases the plasma level of the active drug molecule. There are some instances in which
CYP450 metabolism is required to convert an inactive prodrug to its active metabolite. In these
instances, induction of the specific CYP450 enzyme would enhance this conversion and potentially
increase the desired plasma level of the active metabolite. In contrast, inhibition of the specific
CYP450 enzyme would decrease the desired conversion and subsequently decrease the desired
plasma levels. These types of drug interactions depend on the specific CYP450 isoform needed for
the drug’s metabolism as well as the CYP450 isoforms induced or inhibited by a coadministered
drug. Let’s look at a few examples of the above concepts.
In general, inhibitors or inducers of metabolizing enzymes are classified as strong, moderate,
or weak. Itraconazole, an antifungal drug, is both a substrate and a strong inhibitor of CYP3A4.
Atorvastatin, an HMG CoA reductase inhibitor used to treat dyslipidemia, is primarily metabolized
by CYP3A4. If these two drugs are given together, itraconazole inhibits the metabolism of atorvastatin and increases its plasma levels. Recommendations to avoid serious adverse effects from this drug
interaction include reducing the dose of atorvastatin or replacing atorvastatin with another HMG
CoA reductase inhibitor that does not require CYP3A4 for metabolism. In contrast to itraconazole,
300 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
phenytoin and its prodrug, fosphenytoin, are strong inducers of CYP3A4 and increase the metabolism and decrease the plasma levels of atorvastatin and other drugs requiring this isozyme.
As discussed above, clopidogrel requires CYP2C19 oxidation to be converted to its active
metabolite. The proton pump inhibitors omeprazole, lansoprazole, and pantoprazole are CYP2C19
inhibitors. If these drugs are used in combination with clopidogrel, the serum concentrations of the
active metabolite of clopidogrel may be decreased. Clopidogrel prevents platelet aggregation and
is used to treat acute coronary syndrome and other cardiovascular disorders. Coadministration of
clopidogrel with any of these proton pump inhibitors could potentially impair the effectiveness of
clopidogrel and not provide the needed cardiovascular effects. A final example of CYP450 drug
interactions is seen with tamoxifen. Tamoxifen is used as adjuvant treatment of adult patients with
early stage estrogen receptor-positive breast cancer. While tamoxifen is active, its 4-hydroxyN-desmethyl metabolite (endoxifen) is 30 to 100 times more potent than tamoxifen and provides
the major therapeutic actions of tamoxifen. The addition of the 4-hydroxyl group is the key metabolic step and requires CYP2D6 metabolism (Figure 8-55). Tamoxifen can cause debilitating hot
flashes in women, and this adverse effect can be treated with selective serotonin reuptake inhibitors
(SSRIs). Some SSRIs, especially paroxetine and fluoxetine, inhibit CYP2D. Due to this drug interaction, paroxetine and fluoxetine should not be used in combination with tamoxifen because their use
decreases the formation of the active metabolite and greatly reduces tamoxifen’s efficacy. There
are other SSRIs that do not interfere with CYP2D6 and the formation of endoxifen and are better
choices for treating hot flashes.
FIGURE 8-55.Metabolic conversion of tamoxifen to endoxifen.
SUMMARY OF THE KEY CONCEPTS GOVERNING
METABOLIC TRANSFORMATIONS
The metabolism of drug molecules serves a number of purposes; however, its primary role is to
increase the water solubility of drug molecules and thus enhance their removal from the body.
Metabolism can alter existing functional groups or add new functional groups through Phase I and/
or Phase II metabolic transformations. Oxidation is the most prevalent Phase I metabolic reaction,
and most oxidative transformations are catalyzed by the CYP450 family of enzymes. Other oxidative transformations are catalyzed by FMOs, ADHs, and ALDHs. Hydrolysis and reduction represent
the other two Phase I processes, with hydrolysis being much more prevalent than reduction. Phase
II metabolic transformations involve the addition of endogenous substances to the drug molecule
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in a process known as conjugation. Glucuronic acid conjugation is the most common Phase II
transformation.
When evaluating known metabolic pathways or predicting possible metabolic routes for a
specific drug molecule, the following general concepts should be considered. First, the extent of
metabolic transformation for a given drug molecule is generally proportional to its lipid solubility. Drug molecules that have a higher lipid solubility (i.e., increased log P values) generally require
more extensive metabolism than analogous drug molecules that possess lower lipid solubility. In
many instances, drug molecules that possess a low lipid solubility (or high water solubility) can be
excreted unchanged (i.e., no metabolic transformations). Second, there is no absolute requirement
that a drug molecule undergo both Phase I and Phase II transformations. In some instances, Phase I
transformations are sufficient to provide adequate water solubility for elimination without the need
for Phase II metabolism. In other instances, Phase II conjugation is sufficient due to the presence of
functional groups capable of immediately undergoing conjugation within the parent drug molecule.
Third, a functional group or a drug molecule may be capable of undergoing multiple types of transformations. In these situations, the liver and other metabolic sites perform the minimum number
of transformations necessary to allow for drug molecule elimination or detoxification. Finally, functional groups are more likely to undergo metabolic transformation if they are easily accessible (i.e.,
located at the end of a drug molecule instead of the middle), not electronically deactivated, and not
sterically hindered.
REFERENCES
1. Roche VF, Zito SW, Lemke TL, et al, eds. Foye’s Principles of Medicinal Chemistry. 8th ed.
Philadelphia, PA: Wolters Kluwer; 2020.
2. Beale JM, Block JH, eds. Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical
Chemistry. 12th ed. Philadelphia, PA: Wolters Kluwer/Lippincott Williams & Williams; 2011.
STRUCTURAL ANALYSIS CHECKPOINT
Checkpoint Drug 1: Venetoclax
1. In Chapter 7, you were asked to identify all potential prochiral centers present within the
structure of venetoclax prior to a discussion of metabolic pathways. Now that you have
reviewed all of the normal metabolic pathways, identify those potential prochiral centers
that are valid. Additionally, for each valid prochiral center, identify the metabolic transformation that is required to convert the prochiral center to a chiral center.
2. Listed below are six metabolic transformations. For each metabolic transformation indicate if it is a Phase I or Phase II transformation and if venetoclax has a functional group
302 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
that can participate in the transformation. If you answer YES, then draw the appropriate
metabolite; if you answer NO, then provide a brief explanation as to why this metabolic
transformation is not possible for venetoclax.
Metabolic Pathways
A. Benzylic oxidation
B. Sulfate conjugation
C. Oxidative N-dealkylation
D. Glucuronide conjugation
E. Hydrolysis
F. Alkene oxidation
3. The structure of venetoclax contains three phenyl rings. Although aromatic oxidation could
occur at one or more of these phenyl rings, explain why this metabolic transformation has
a low probability of occurring.
4. Shown below is a potential metabolite of venetoclax. Identify the metabolic transformations required to produce this metabolite. Please note that some steps must occur prior to
other steps while other steps are completely independent of one another.
Checkpoint Drug 2: Elamipretide
1. Consider the structure of elamipretide and determine if the drug can be excreted without
the need for any metabolic transformation. Provide a brief structural rationale for your
answer.
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2. Based on your structural evaluation of elamipretide, does a Phase I metabolic transformation need to occur before a Phase II conjugation reaction occurs? If so, then identify which
Phase I transformation must occur and then which Phase II conjugation reaction can occur.
If not, then list the name of the functional group(s) that can undergo a Phase II conjugation
reaction and the specific Phase II transformation associated with each group.
3. There are a number of Phase I transformations that could occur on elamipretide, including
on more than one prochiral center. List ALL possible Phase I transformations and identify
which Phase I transformation(s) could convert a prochiral carbon to a chiral carbon.
4. The structure below is one of the prodrug forms of elamipretide that could be considered
to improve metabolic stability. Which metabolic transformations must occur to produce
the active form of the drug?
REVIEW QUESTIONS
1. Consider the structure of flesinoxan drawn below and do the following:
A. List all of the Phase I metabolic transformations possible for flesinoxan.
B. Draw all of the possible products created when the functional group that is boxed
undergoes a Phase I metabolic transformation.
Describe how you would modify the structure of flesinoxan to prevent Phase II
C.
metabolism.
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