Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5323_Библиотеки_им_академика_М_И_Перельмана
.pdf
264 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
N-Oxidation of secondary amines can sequentially form hydroxylamines, imines, nitrones, and
aldehydes. On the rare occasion that both carbon atoms attached to the secondary amine lack a
hydrogen atom, then only a hydroxylamine can be formed. An example of what could occur with
the N-oxidation of a secondary amine is shown in Figure 8-18 with encainide. Similar to primaquine,
the original hydroxylamine can undergo a dehydration reaction to yield an imine. Hydrolysis of the
imine opens the ring and produces the same metabolic product that can be directly formed via
N-dealkylation. Further oxidation of the imine produces a nitrone.
FIGURE 8-18.CYP450 or FMO catalyzed
N
-oxidation of the secondary amine of encainide.
Tertiary amines as well as heterocyclic amines can be directly oxidized to form N-oxides. Shown
in Figure 8-19 are the structures of prochlorperazine, a drug with multiple tertiary amines, and zaleplon, a drug with multiple heterocyclic amines. A single nitrogen atom has been chosen to illustrate
N-oxidation for both of these drugs. Please note that this metabolic transformation could also occur
at the other nitrogen atoms on these drugs. As with other examples of N-oxidation, there are other
metabolic transformations that could occur, some of which may be more prevalent. In the case of
prochlorperazine, N-dealkylation and aromatic hydroxylation followed by Phase II conjugation are
much more prevalent than N-oxidation. The examples here are provided to illustrate metabolic
pathways that could possibly occur.
CH 8 - DRUG METABOLISM 265
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
FIGURE 8-19.Examples of
CYP450 or FMO enzymes.
In some instances, N-oxidation can lead to the formation of potentially toxic metabolites. This
is especially true if adjacent functional groups help to catalyze the formation of a highly electrophilic
intermediate. A good example of this is seen with acetaminophen (Figure 8-20). When taken in normal doses, approximately 1% to 2% of acetaminophen undergoes N-oxidation. Due to the presence
of the para phenol group, there is a subsequent dehydration and the formation of a highly reactive
electrophile. At normal doses, the concentration of this reactive intermediate is low enough that it
is readily deactivated by glutathione conjugation; however, in acetaminophen overdoses, saturation
of conjugation pathways can lead to liver damage and death.
N
-oxidation of tertiary and heterocyclic amines catalyzed by
FIGURE 8-20.
intermediate.
N
-Oxidation of acetaminophen and the generation of a potentially toxic
266 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
Oxidation of Functional Groups with Carbon-Oxygen Bonds
Hydroxyl groups that were initially present within the structure of a drug molecule or were added as a
result of the oxidation of hydrocarbon rings and chains can undergo oxidation to produce aldehydes,
ketones, and carboxylic acids. As previously mentioned, ADH enzymes catalyze the oxidation of primary and secondary hydroxyl groups to aldehydes and ketones, respectively, while ALDH enzymes
catalyze the oxidation of aldehydes to carboxylic acids. These dehydrogenase enzymes are distinct
from CYP450 enzymes and are not affected by drugs that induce or inhibit CYP450 isozymes.
Primary hydroxyl groups are initially oxidized to an aldehyde and then to a carboxylic acid.
Additionally, aldehydes generated via N-dealkylation or oxidative deamination can also undergo
additional oxidation to produce carboxylic acids. It is rare that oxidation stops at the aldehyde.
Two examples are shown in Figure 8-21. The structure of albuterol already contains three hydroxyl
FIGURE 8-21.Oxidation of primary hydroxyl groups to aldehydes and carboxylic acids
(see boxes).
CH 8 - DRUG METABOLISM 267
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
groups. The primary hydroxyl group can be initially oxidized to an aldehyde and then to a carboxylic acid. The structure of tolmetin does not initially contain a hydroxyl group; however, benzylic
oxidation of the para methyl group results in the formation of a primary hydroxyl group. Similar to
albuterol, this primary hydroxyl group can be further oxidized to an aldehyde and then to a carboxylic acid.
Secondary hydroxyl groups can be oxidized to ketones. Two examples are shown in Figure 8-22.
The secondary hydroxyl group originally present within the structure of albuterol can be directly
oxidized to a ketone whereas a ketone metabolite of pentobarbital can occur following an initial ω-1
oxidation. Tertiary hydroxyl groups cannot be further oxidized.
FIGURE 8-22.Oxidation of secondary hydroxyl groups to ketones by ADH (see boxes).
Similar to N-dealkylation, ethers can be metabolized via oxidative O-dealkylation (henceforth
denoted as O-dealkylation) to more water-soluble hydroxyl groups. The mechanism of this metabolic transformation is shown below. Please note that this mechanism is very similar to that discussed for N-dealkylation and that it requires a hydrogen atom to be attached to at least one of
the carbon atoms that are adjacent to the ether oxygen atom. The only mechanistic difference is
that the initial intermediate is a hemiacetal instead of a carbinolamine; however, similar to a carbinolamine, a hemiacetal is unstable and subsequently reacts to form a hydroxyl group and either an
aldehyde or a ketone.
Examples of drugs that can undergo O-dealkylation are shown in Figure 8-23. Similar to
N-dealkylation, smaller alkyl groups are more likely to undergo O-dealkylation than are larger
groups. Methyl ethers (i.e., methoxy groups), as exemplified by trimethoprim, often undergo
O-dealkylation. Oxidation of fluoxetine at the benzylic position produces a hemiacetal that can lead
268 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
FIGURE 8-23.Examples of oxidative
(see boxes).
to O-dealkylation. Due to steric hindrance, this O-dealkylation represents only a minor metabolic
pathway for fluoxetine, with aromatic hydroxylation and N-demethylation being its two most common metabolic transformations. Again, the primary objective of these examples is to expose the
reader to all of the possible metabolic routes.
The O-dealkylation of fluoxetine also helps to reemphasize a key point that was previously
discussed with both benzylic oxidation and the N-dealkylation of nicardipine. The benzylic carbon
atom of fluoxetine is already attached to a heteroatom; therefore, oxidation at this site produces a
hemiacetal, not a stable hydroxyl group. Thus, oxidation at this carbon atom is correctly described
as O-dealkylation and not benzylic oxidation.
O
-dealkylation catalyzed by CYP450 enzymes
Oxidation of Functional Groups Containing Sulfur Atoms
Four main types of oxidation can occur with functional groups that contain a sulfur atom: S-dealkylation,
S-oxidation, dimerization, and desulfuration. The mechanism of S-dealkylation is identical to N- and
O-dealkylation, requires that the adjacent carbon atom is attached to a hydrogen atom, and is more
likely to occur with smaller alkyl groups than larger alkyl groups. This metabolic route is not seen
very often due to the limited number of drug molecules that contain a thioether. Examples are
shown in Figure 8-24 with thiethylperazine and ranitidine. This metabolic transformation produces
a thiol (or sulfhydryl group) and either an aldehyde or ketone.
Thioethers can also undergo direct S-oxidation to produce sulfoxides and sulfones. These reactions are normally catalyzed by FMO enzymes rather than CYP450 enzymes. Thus, thiethylperazine
and ranitidine can alternatively be converted to sulfoxides or sulfones (Figure 8-25). Please note
that the formation of sulfoxides and sulfones occurs in a sequential manner, with the formation of a
sulfoxide occurring first. Further oxidation of the sulfoxide produces a sulfone. Please note that thiethylperazine contains two thioethers. Although S-oxidation is only shown at one of these, it could
also occur at the other thioether.
Drug molecules that contain sulfhydryl groups can be oxidized to disulfides. Similar to
S-oxidation, FMO enzymes normally catalyze this metabolic transformation. An example of this is
seen below with captopril. This particular oxidation is responsible for the relatively short duration of
CH 8 - DRUG METABOLISM 269
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
FIGURE 8-24.Examples of
S
-dealkylation catalyzed by CYP450 enzymes.
FIGURE 8-25.Examples of
S
-oxidation catalyzed by FMO enzymes.
270 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
action of captopril. Similar to thioethers, sulfhydryl groups are only seen in a very limited number
of drug molecules.
Finally, drug molecules that contain a thiocarbonyl (also known as a thioketone) can undergo
a desulfuration reaction in which the thiocarbonyl is converted to a carbonyl. Similar to the above
metabolic transformations, only a limited number of functional groups contain a thiocarbonyl. Two
examples are shown in Figure 8-26.
FIGURE 8-26.Examples of desulfuration.
Oxidative Dehalogenation
This type of oxidation can remove halogens from aliphatic chains and aliphatic rings but not from
aromatic rings. Similar to all other oxidations, halogens can only be removed from carbon atoms
that are also attached to a hydrogen atom. As such, a trifluoromethyl group (CF3) cannot undergo
this metabolic transformation. The general mechanism of this oxidation is shown below. The final
product depends on adjacent atoms and functional groups.
CH 8 - DRUG METABOLISM 271
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
If the R1 group is not a halogen, then the product is generally either an aldehyde or a ketone;
however, if the R1 group is a halogen, a highly reactive acyl halide is formed as an intermediate.
Nucleophilic displacement of the halide by a water molecule produces a stable and water-soluble
carboxylic acid. An example is shown in Figure 8-27A with chloramphenicol. It should be noted that
acyl halides are also capable of reacting with cellular biomolecules, typically resulting in hepatotoxicity. This has been observed with fluorinated hydrocarbons (e.g., halothane, enflurane, isoflurane) used to induce general anesthesia. The formation of acyl halides and their reaction with tissue
proteins has been shown to be responsible for hepatotoxicity of this class of agents. An example is
shown in Figure 8-27B with enflurane. Please note that the first two steps are identical to those for
chloramphenicol. The key difference is that instead of reacting with a molecule of water, the reactive
intermediate reacts with a cellular biomolecule.
FIGURE 8-27.Examples of oxidative dehalogenation catalyzed by CYP450 enzymes.
272 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
PHASE I METABOLISM: REDUCTION
Reduction is the opposite of oxidation and involves the gain of electrons and a decrease in the oxidation state of an atom or molecule. Similar to oxidation, the changes in electrons and oxidation states
are not always easy to discern in a drug molecule; however, all of the reductions discussed below
involve a gain of hydrogen by the reduced functional group. Reduction is the least common Phase
I metabolic pathway because only a few functional groups are susceptible to this metabolic transformation and some of these functional groups, such as azo and nitro groups, are only present on
a very limited number of drug molecules. Enzymes that catalyze reduction-based metabolic transformations are found in the liver, kidney, and other tissues. Aldehydes and ketones can be reduced
by aldo-keto reductase enzymes or oxidoreductase enzymes whereas azo and nitro groups can be
reduced by azoreductase and nitroreductase enzymes, respectively. Additionally, bacteria present
within the GI tract are capable of reducing these functional groups. All of these enzymes require
NADPH as the reducing species.
Reduction of Aldehydes and Ketones
Aldehydes are generally metabolically unstable and are rarely present on parent drug molecules. As
previously discussed, they can be formed via oxidative deamination, N-dealkylation, O-dealkylation,
and S-dealkylation. They are primarily oxidized to carboxylic acids; however, in some instances, they
can be reduced to a hydroxyl group. An example is shown in Figure 8-28 with duloxetine. Duloxetine
can form an aldehyde intermediate by first undergoing N-dealkylation and then oxidative deamination or by directly undergoing oxidative deamination. The resulting aldehyde can be either oxidized
to a carboxylic acid or reduced to a primary hydroxyl group.
Ketones that are initially present in a drug molecule or that are introduced by oxidative metabolism can be reduced to secondary hydroxyl groups. Similar to the hydrocarbon oxidations that
added a hydroxyl group to a prochiral center, the reduction of ketones often generates only one
FIGURE 8-28.Metabolic routes for duloxetine.
CH 8 - DRUG METABOLISM 273
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
stereoisomer or generates one stereoisomer as a major metabolite and the other as a minor metabolite. Interestingly, ketones that are formed via the oxidation of enantiomerically pure secondary
hydroxyl groups can be reduced to form the opposite enantiomer. This reversible oxidation of a secondary hydroxyl group to a ketone, followed by reduction of the ketone back to a secondary hydroxyl
group, is not uncommon, and drug molecules containing these functional groups are often eliminated as Phase II conjugates of the hydroxyl group. Two examples of ketone reduction are shown in
Figure 8-29. The R,S isomer is the major metabolic reduction product of warfarin, with the R,R iso-
mer being a minor metabolite. This is an example of stereoselective drug metabolism. In contrast,
the S,S isomer is the only metabolic reduction product seen in methadone. This is an example of
stereospecific drug metabolism.
FIGURE 8-29.Examples of ketone reduction by aldo-keto reductase enzymes.
Reduction of Azo and Nitro Groups
Azo groups, like that seen below with balsalazide, can be reduced to produce two aromatic amines.
Often, this reduction is catalyzed by bacteria that reside within the GI tract.
Соседние файлы в папке Библиотека им академика М.И. Перельмана