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_5434_Библиотеки_им_академика_М_И_Перельмана
.pdf
The most frequent reaction of the primary amines is the oxidative deamination by
the action of monoaminoxidase in the unsubstituted amines in α.
7.5.1.2 Reduction reactions
Although the main metabolic pathway of drugs in mammals is oxidation, certain com-
pounds whose functional groups are the azo, nitro, and carbonyl groups tend to be
biotransformed by reduction to other functional groups such as amino and hydroxyl,
directly susceptible to conjugation.
Example: Methadone (Fig. 7.8).
7.5.1.3 Hydrolysis reactions
It is the immediate form of metabolism of esters and amides and takes place by the
action of esterases and amidases that are very widespread in the organism.
Example: Procaine (Scheme 7.4).
The amides hydrolyze more slowly than the esters; e.g. procainamide is more stable
than procaine against hydrolysis (longer half-life) (Scheme 7.5).
Fig. 7.8: Reductive metabolism of methadone.
Scheme 7.4: Metabolic hydrolysis of procaine.
Scheme 7.3: Oxidative deamination of dopamine.
142 7 Metabolic processes in drugs: other methodologies
https://t.me/medicina_free
7.5.2 Phase II reactions
7.5.2.1 Conjugation reactions
They occur when the metabolites resulting from Phase I processes are not sufficiently
water-soluble to be eliminated by urine. The purpose is to form more hydrophilic and
rapid renal elimination metabolites. They take place with endogenous compounds
(glucuronic acid, sulfate, glutathione, and certain amino acids).
7.5.2.1.1 The anomeric effect
The reason to explain the anomeric effect is outlined in Scheme 7.6.
7.5.2.1.1.1 Acyclic and cyclic forms of glucose
Alcohols are added to the carbonyl group of aldehydes in a fast and reversible way
giving hemiacetals; this can be done intramolecularly when alcohols and carbonyl
groups are at appropriate distances. Therefore, monosaccharides in aqueous solution
are in equilibrium between the cyclic or hemiacetal form and the acyclic one, al-
though the equilibrium is usually shifted toward the cyclic form since this is more
stable.
Cyclic forms can be represented by the Haworth projection and the chair confor-
mation (Scheme 7.7).
The OH at C5 reacts with the carbonyl group to give rise to a six-membered ring
because it is more stable than the seven-membered one, and consequently the Ha-
worth projection is depicted in Scheme 7.8.
7.5.2.1.1.2 Acyclic and cyclic forms of
D-glucose
Glucose is usually present in solid form as a closed pyran ring. In aqueous solution,
on the other hand, it is an open chain to a small extent and is present predominantly
as an α-orβ-pyranose, which interconvert (Scheme 7.9).
7.5.2.1.1.3 Molecular orbitals
To construct molecular orbitals (MOs) we need to combine the atomic orbitals of
atoms that make up the molecule. This approach is known as the linear combination
of atomic orbitals. Atomic orbitals are wave functions (Scheme 7.10), and the different
Scheme 7.5: Hydrolysis of procainamide.
7.5 Metabolism 143
https://t.me/medicina_free
wave functions can be combined together in the way waves combine: they can add
together constructively (in-phase) or destructively (out-of-phase).
Atomic orbitals can combine in the same way: in-phase or out-of-phase. Using
two 1s orbitals drawn as circles with dots to mark the nuclei and shading to represent
phase, we can combine them in-phase, that is, add them together, or out-of-phase
when they cancel each other in a nodal plane in the center between the two nuclei.
The resulting atoms are molecular rather than atomic orbitals (Scheme 7.11).
Scheme 7.6: The anomeric effect.
144 7 Metabolic processes in drugs: other methodologies
https://t.me/medicina_free
Scheme 7.7: Representation of open and cyclic forms.
Scheme 7.8: Cyclic forms of D-glucose.
7.5 Metabolism 145
https://t.me/medicina_free
Scheme 7.9: Cyclic and acyclic forms of D-glucose.
Scheme 7.10: Wave functions.
146 7 Metabolic processes in drugs: other methodologies
https://t.me/medicina_free
7.5.2.1.1.3.1 The hydrogen molecule
In the bonding MO, the electrons can be shared between the two nuclei, and this low-
ers their energy relative to the 1s atomic orbital. Electrons in the σ
✶
orbital do not
help bond; in fact, they hinder the bonding (Scheme 7.12).
Scheme 7.11: Molecular orbitals.
Scheme 7.12: The hydrogen molecule.
7.5 Metabolism 147
https://t.me/medicina_free
7.5.2.1.1.3.2 The anomeric effect
The anomeric effect is a stereoelectronic effect that describes the tendency of heter-
oatomic substituents adjacent to a heteroatom within a cyclohexane ring to prefer the
axial orientation instead of the less hindered equatorial orientation that would be ex-
pected from steric considerations (Fig. 7.9).
In the above case, the methoxy group on the cyclohexane ring (top) prefers the equa-
torial position. However, in the tetrahydropyran ring (bottom), the methoxy group
prefers the axial position. This is because in the cyclohexane ring, the anomeric effect
is not observed, and steric effects dominate the observed substituent position. In the
tetrahydropyran ring, because of the endocyclic oxygen atom, the anomeric effect
contributes and stabilizes the observed substituent position.
A widely accepted explanation is that there is a stabilizing interaction (hypercon-
jugation) between the unshared electron pair on the heteroatom (the endocyclic one
in a sugar ring) and the σ
✶
orbital for the axial (exocyclic) C–X bond. This causes the
molecule to align the donating lone pair of electrons to the σ
✶
orbital lowering the
overall energy of the system and causing more stability. The fact that an antibonding
orbital contributes to the destabilization of a molecule does not mean that an anti-
bonding orbital is never occupied (Fig. 7.10).
Compounds exhibiting an anomeric effect have a longer (and therefore weakened)
bond outside the ring and a shorter, stronger C–O bond within the ring (Fig. 7.11).
Fig. 7.9: The anomeric effect.
Fig. 7.10: The anomeric effect.
148 7 Metabolic processes in drugs: other methodologies
https://t.me/medicina_free
Another accepted explanation for the anomeric effect is the equatorial configuration
that has the dipoles involving both heteroatoms partially aligned, and therefore repel-
ling each other. By contrast, the axial configuration has these dipoles roughly oppos-
ing, thus representing a more stable and lower energy state (Fig. 7.12).
7.5.2.2 Glucuronides
Conjugation reactions take place by the reaction of existing polar groups in a drug,
and H
2
SO
4
, glucuronic acid, glutathione, sugars, or amino acids such as glycine, and
also acetylation and methylation giving directly excretable compounds. Conjugation
with glucuronic acid is probably the most important of all Phase II reactions. This is
probably because there is a good supply of glucuronic acid in the body. Numerous
alcohols, phenols, amines, thiols, and some carboxylic acids are metabolized by this
pathway. The xenobiotic reacts with the activated form of glucuronic acid, glucuronic
acid uridine diphosphate (UDPGA), to form a glucuronide conjugate very soluble in
water (Scheme 7.13). The reaction is catalyzed by uridine diphosphate glucuronyl
transferases (UDPG transferases).
The term “Walden inversion” is used to describe the stereochemical outcome of
aliphatic bimolecular nucleophilic substitution reactions. A bimolecular nucleophilic
substitution reaction at a chiral carbon atom produced a product that has the opposite
stereochemistry from that of the reactant. This requires the nucleophile to approach
the chiral atom from the side opposite to the leaving group (Scheme 7.13).
Example: Paracetamol conjugated with glucuronic acid (Scheme 7.14).
The reaction takes place on the anomeric carbon of the glucuronic acid giving
rise to acetals.
7.5.2.3 Conjugation with glycine
Certain amino acids participate in the reaction of Phase II metabolites from aromatic car-
boxylic acids. Glycine is the amino acid that is commonly involved in these conjugations.
O
OMe
O
OMe
(-)
(+)
Fig. 7.11: One interpretation of the anomeric effect.
O
H
O
H
OMe
OMe
O
Fig. 7.12: A second interpretation of the anomeric
effect.
7.5 Metabolism 149
https://t.me/medicina_free
Scheme 7.13: Mechanism of formation of glucuronide conjugates. UTP is uridine triphosphate and X is O
(alcohols and phenols), S (thiols), or NH (amines).
O
HO
HO
COOH
OH
O NHCOCH
Paracetamol
O-glucuronide
O
HO
HO
COOH
HO
O
P
O
OH
O
P
OH
O
O
O
HO
OH
N
NH
O
O
UDP-glucuronic acid
NHCOCH
HO
+
UDP
(Uridine
diphosphate)
Scheme 7.14: Paracetamol conjugated with glucuronic acid.
150 7 Metabolic processes in drugs: other methodologies
https://t.me/medicina_free
Example: Scheme 7.15.
Benzoic acid is introduced into the body through diet, as it is widely used as a preser-
vative (both in its acid form and as a sodium, potassium, or calcium salt), although it
is not a drug. Hippuric acid (from Greek: Hyppos, horse; ouron, urine) is an organic
acid found in the urine of horses and other herbivores.
7.5.2.4 Acetylation
Acetylation is the main route of metabolization for amino groups and is mediated by
acetyl-CoA.
Example: Acetylation of procainamide (Scheme 7.16).
The half-life of N-acetylprocainamide is twice than that of procainamide and has no
undesirable side effects.
Example: Metabolism of Aspirin
®
(Scheme 7.17).
7.5.2.5 Conjugation reactions with glutathione
Glutathione is a tripeptide containing a thiol group of great importance in the detoxi-
fication of drugs and xenobiotics. (A xenobiotic is a chemical substance found within
an organism that is not naturally produced or expected to be present within the or-
ganism.) In the body, an equilibrium exists between the reduced form (GSH) and the
oxidized form (GS–GS). Conjugation reactions of GSH are catalyzed by glutathione
transferases. The conjugative reactivity of GSH is due to its thiol group (pK
a
9.0),
which makes it a very effective nucleophile. The nucleophil ic character is enhanced
by deprotonation to a thiolate form. It reacts with halides, epoxides, or double acti-
vated bonds (Fig. 7.13).
COOH
O
N
H
COOH
Benzoic acid
Hippuric
acid
N
-Acyltransferase
Scheme 7.15: Metabolization of benzoic acid.
CONHCH
2
CH
2
NEt
2
H
2
N
CONHCH
2
CH
2
NEt
2
H
3
COCHN
N
-Acetyltransferase
Procainamide
Scheme 7.16: Acetylation of procainamide.
7.5 Metabolism 151
https://t.me/medicina_free
Соседние файлы в папке Библиотека им академика М.И. Перельмана