Metabolic Changes of Drugs and Related Organic Compounds - PowerPoint Presentation

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Metabolic Changes of Drugs and Related Organic Compounds

Lecture /

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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 trans- 1,2-dihydrodiols.In addition, several epoxides undergo GSH conjugation.

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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 10,11-dihydroxycarbamazepine, an important urinary metabolite in humans.3

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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

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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

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The presence of the

dihydroxy

metabolite (

secodiol) of secobarbital, but not the epoxide product, has been reported in humans.6

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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

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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

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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

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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

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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

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T

he

“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, anti-inflammatory agent celecoxib and β-adrenergic blocker metoprolol undergo benzylic oxidation.

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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 C-3). 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.

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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

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Oxidation at Carbon Atoms α

-

to

Carbonyls and IminesThe 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.

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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

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Oxidation at Aliphatic and AlicyclicCarbon 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

.

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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-n-propylglutaric acid.20

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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

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Biotransformation of

the antihypertensive agent

minoxidil

yields the 4`-hydroxypiperidyl metabolite.22

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Oxidation InvolvingCarbon–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

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Oxidative N-, O-, and S-

dealkylation

as well as

oxidative deamination reactions fall under this mechanistic pathway.25

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2. Hydroxylation or oxidation of the heteroatom (

N, S

only

, e.g., N-hydroxylation, N-oxide formation, sulfoxide, and sulfone formation).26

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OXIDATION INVOLVING CARBON–NITROGEN SYSTEMS.

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END

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