Download N.9 – Metabolic Changes of Drugs and Related

Metabolic Changes of Drugs and
Related Organic Compounds
Lecture / 2
Oxidation of Olefins





The metabolic oxidation of olefinic carbon–carbon double
bonds leads to the corresponding epoxide (or oxirane).
Epoxides derived from olefins generally tend to be somewhat
more stable than the arene oxides formed from aromatic
compounds.
A few epoxides are stable enough to be directly measurable
in biological fluids (e.g., plasma, urine).
Like their arene oxide counterparts, epoxides are susceptible
to enzymatic hydration by epoxide hydrase to form trans1,2-dihydrodiols.
In addition, several epoxides undergo GSH conjugation.
2
A well-known example of olefinic epoxidation is the metabolism
of the anticonvulsant drug carbamazepine (Tegretol) to
carbamazepine-10,11-epoxide.
 The epoxide is reasonably stable and can be measured
quantitatively in the plasma of patients receiving the parent drug.
 The epoxide metabolite may have marked anticonvulsant activity
and, therefore, may contribute to the therapeutic effect of the
parent drug.
 Subsequent hydration of the epoxide produces 10,11dihydroxycarbamazepine, an important urinary metabolite in
humans.

3
Epoxidation of the olefinic 10,11-double bond in the
antipsychotic agent protriptyline and in the H1-histamine
antagonist cyproheptadine also occurs.
 The epoxides formed from the biotransformation of an olefinic
compound are minor products, because of their further
conversion to the corresponding 1,2-diols.

4
The dihydroxyalcofenac is a major human urinary metabolite of
the anti-inflammatory agent alclofenac.
 The epoxide metabolite from which it is derived, however, is
present in minute amounts.

5

The presence of the dihydroxy metabolite (secodiol) of
secobarbital, but not the epoxide product, has been reported
in humans.
6
Why Aflatoxin B1 is carcinogenic?
This naturally occurring carcinogenic agent contains an olefinic
(C2–C3) double bond adjacent to a cyclic ether oxygen.
 The hepatocarcinogenicity of aflatoxin B1 has been clearly
linked to its metabolic oxidation to the corresponding 2,3-oxide,
which is extremely reactive.
 Extensive in vitro and in vivo metabolic studies indicate that
this 2,3-oxide binds covalently to DNA, RNA, and proteins.

7
Other olefinic compounds, such as vinyl chloride, stilbene, and
the carcinogenic estrogenic agent diethylstilbestrol undergo
metabolic epoxidation.
 The corresponding epoxide metabolites may be the reactive
species responsible for the cellular toxicity seen with these
compounds.

8




An interesting group of olefin-containing compounds
causes the destruction of CYP.
Compounds belonging to this group include
allylisopropylacetamide, secobarbital, and the volatile
anesthetic agent fluroxene.
It is believed that the olefinic moiety present in these
compounds is activated metabolically by CYP to form a
very reactive intermediate that covalently binds to the
heme portion of CYP.
Long-term administration of the above mentioned three
agents is expected to lead to inhibition of oxidative drug
metabolism, potential drug interactions, and prolonged
pharmacological effects.
9
10
Oxidation at Benzylic Carbon Atoms

Carbon atoms attached to aromatic rings (benzylic
position) are susceptible to oxidation, thereby forming the
corresponding alcohol (carbinol) metabolite.

Primary alcohol metabolites are often oxidized further to
aldehydes and carboxylic acids (CH2OH → CHO →
COOH), and secondary alcohols are converted to ketones
by alcohol and aldehyde dehydrogenases.

Alternatively, the alcohol may be conjugated directly
with glucuronic acid.
11
The benzylic carbon atom present in the oral
hypoglycemic agent tolbutamide is oxidized extensively
to the corresponding alcohol and carboxylic acid.
 Both metabolites have been isolated from human urine.

12

The “benzylic” methyl group in the anti-inflammatory
agent tolmetin undergoes oxidation to yield the
dicarboxylic acid product as the major metabolite in
humans.

The selective cyclooxygenase 2 (COX-2) inhibitor, antiinflammatory agent celecoxib and β-adrenergic blocker
metoprolol undergo benzylic oxidation.
13
Oxidation at Allylic Carbon Atoms







Microsomal hydroxylation at allylic carbon atoms is commonly
observed in drug metabolism.
An illustrative example of allylic oxidation is given by the
psychoactive component of marijuana, Δ 1 -tetrahydrocannabinol.
This molecule contains three allylic carbon centers (C-7, C-6, and C3).
Allylic hydroxylation occurs extensively at C-7 to yield 7-hydroxy- Δ
1-THC as the major plasma metabolite in humans.
Pharmacological studies show that this 7-hydroxy metabolite is as
active as, or even more active than, Δ 1-THC.
Hydroxylation also occurs to a minor extent at the allylic C-6 position
to give both the 6-α and 6-β hydroxy metabolites.
Metabolism does not occur at C-3, presumably because of steric
hindrance.
14
15
The antiarrhythmic agent quinidine is metabolized by allylic
hydroxylation to 3-hydroxyquinidine, the principal plasma
metabolite found in humans.
 This metabolite shows significant antiarrhythmic activity in
animals and possibly in humans.

16
Oxidation at Carbon Atoms α- to
Carbonyls and Imines
The mixed-function oxidase system also oxidizes carbon atoms
adjacent (i.e.,α ) to carbonyl and imino (C = N) functionalities.
 An important class of drugs undergoing this type of oxidation is
the benzodiazepines.
 For example, diazepam, flurazepam, and nimetazepam are
oxidized to their corresponding 3-hydroxy metabolites.
 The C-3 carbon atom undergoing hydroxylation is α to both a
lactam carbonyl and an imino functionality.

17
For diazepam, the hydroxylation reaction proceeds with
remarkable stereoselectivity to form primarily (90%)
3-hydroxydiazepam (also called N-methyloxazepam), with the
(S) absolute configuration at C-3.
 Further N-demethylation of the latter metabolite gives rise to the
pharmacologically active 3(S)-oxazepam.

18
Oxidation at Aliphatic and Alicyclic
Carbon Atoms
Alkyl or aliphatic carbon centers are subject to mixed
function oxidation.
 Metabolic oxidation at the terminal methyl group often is
referred to as ω-oxidation, and oxidation of the penultimate
carbon atom (i.e., next-to-the-last carbon) is called ω–1
oxidation.
 The initial alcohol metabolites formed from these enzymatic
ω and ω–1 oxidations are susceptible to further oxidation to
yield aldehyde, ketones, or carboxylic acids.
 Alternatively, the alcohol metabolites may undergo
glucuronide conjugation.

19
Aliphatic ω and ω–1 hydroxylations commonly take place in
drug molecules with straight or branched alkyl chains.
 Thus, the antiepileptic agent valproic acid undergoes both ω
and ω–1 oxidation to the 5-hydroxy and 4-hydroxy
metabolites, respectively.
 Further oxidation of the 5-hydroxy metabolite yields 2-npropylglutaric acid.

20

Omega and ω–1 oxidation of the isobutyl moiety present in
the anti-inflammatory agent ibuprofen yields the
corresponding carboxylic acid and tertiary alcohol
metabolites.
21

Biotransformation of the antihypertensive agent
minoxidil yields the 4`-hydroxypiperidyl metabolite.
22
23
Oxidation Involving
Carbon–Heteroatom Systems




Nitrogen and oxygen functionalities are commonly
found in most drugs and foreign compounds; sulfur
functionalities occur only occasionally.
Metabolic oxidation of carbon–nitrogen, carbon–
oxygen, and carbon–sulfur systems principally involves
two basic types of biotransformation processes:
1. Hydroxylation of the α -carbon atom attached directly
to the heteroatom (N, O, S).
The resulting intermediate is often unstable and
decomposes with the cleavage of the carbon–heteroatom
bond:
24

Oxidative N-, O-, and S-dealkylation as well as oxidative
deamination reactions fall under this mechanistic
pathway.
25

2. Hydroxylation or oxidation of the heteroatom
(N, S only, e.g., N-hydroxylation, N-oxide
formation, sulfoxide, and sulfone formation).
26

OXIDATION INVOLVING CARBON–
NITROGEN SYSTEMS.
27
END
28