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

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.

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.

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.

The presence of the dihydroxy metabolite (secodiol) of secobarbital, but not the epoxide product, has been reported in humans.

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.

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.

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.

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.

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.

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

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.

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.

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.

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.

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.

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.

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.

Biotransformation of the antihypertensive agent minoxidil yields the 4`-hydroxypiperidyl metabolite.

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:

Oxidative N-, O-, and S-dealkylation as well as oxidative deamination reactions fall under this mechanistic pathway.

2. Hydroxylation or oxidation of the heteroatom (N, S only, e. g 2. Hydroxylation or oxidation of the heteroatom (N, S only, e.g., N-hydroxylation, N-oxide formation, sulfoxide, and sulfone formation).

OXIDATION INVOLVING CARBON– NITROGEN SYSTEMS.

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