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6Drug metabolism 129

Direct deamination of 2°

amine is an exception [52]. Some 2° alicyclic amines like phenmatrizine (anorectic agent) and methylphenidate are metabolized to their corresponding lactam derivatives [53]. Metabolic N-oxidation of 2° clic amines leads to several N-oxygenated products. Hydroxylation of 2°

aliphatic and alicy-

amines such as N-benzylamphetamine, methyl phenindate and phenmetrazine (Fig.6.32) generates corresponding N-hydroxylamine metabolites which are susceptible for further oxidation to form corresponding nitrone derivatives [54]. In comparison with oxida-

H3C

5C6

N H

5C6

H3C

5C6

Phenmetrazine Carbinolamine 3–oxyphenmetrazine

(lactum)

COOCH

COOH

Hydrolysis

Methyl phenindate Ritalinic acid

6 –oxoritalinic acid(lactam)

Fig. 6.32: Hydroxylation of phenmetrazine and methyl phenindate.

Amphetamine

α–carbon

hydroxylation

O CH

–NH

Phenyl acetone

Carbinolamine

N-hydroxy phenteramine

P-hydroxyphenteramine

Phenteramine

N-hydroxylation

Aromatic para hydroxylation

No α-carbon hydroxylation No Oxidative deamination

COOH

Fig. 6.33: α-substituents determining carbon or nitrogen oxidations.

130 Komarla Kumarachari Rajasekhar*

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tive dealkylation and deamination, N-oxidation occurs to a much lesser extent for 2° amines. Primary aliphatic amines are metabolized either by oxidative deamination (carbinolamine pathway) or by N-oxidation [55]. Examples for endogenous primary amines are neurotransmitters like dopamine, tryptamine, norepinephrine and serotonin. In amphetamine and phenteramine (Fig.6.33), structural features, especially the α-substituents of the primary amine, often determine whether carbon or nitrogen oxidations will occur [56].

6.3.7.1.2 Aromatic amines and heterocyclic nitrogen compounds

Metabolism of aromatic amines parallels the carbon and nitrogen oxidation reactions of aliphatic amines [57]. F

ertiary aromatic amines, such as N,N-dimethylaniline,

or t

oxidative N-dealkylation as well as N-oxide formation take place (Fig.6.34).

Secondary aromatic amines may undergo N-dealkylation or N-hydroxylation to give the corresponding N-hydroxylamines. Further oxidation of the N-hydroxylamine leads to nitrone products, which in turn may be hydrolyzed to primary hydroxylamines (Fig.6.35).

CH2OH

–HCHO

Secondary amine metabolite

Tertiary amine

RON

N – Oxide metabolite

Carbinolamine metabolite

Fig. 6.34: Oxidative N-dealkylation and N-oxide formation in tertiary amines.

CH2R

2° amine Nitrone

Hydroxylamine

CH2R

Oxidation

Hydroxylamine

Fig. 6.35: N-dealkylation and N-hydroxylation in secondary amines.

CH2R

–

6Drug metabolism 131

Tertiary and secondary aromatic amines are rarely seen in medicinal agents. Primary aromatic amines are found in many drugs as well as in reduced metabolites of aromatic nitro compounds, azo compounds, and aromatic amides [58, 59]. N-Oxidation of primary aromatic amines like dapsone (Fig.6.36) generates the N-hydroxylamine metabolites. These hydroxylamine derivatives may undergo either further oxidation to nitroso metabolites or conjugation with glucuronic acid [60].

Several aromatic amines like dapsone after bioconversion into N-hydroxy deriva-

tives cause methemoglobinemia toxicity. N-hydroxyl amine metabolites the oxidized

NHOH N=O

Aniline derivative Hydroxyl amine Nitroso metabolite

R.NH

R.NH SO

Dapsone R=H N-acetyl dapsone R=COCH

Fig. 6.36: N-Oxidation of dapsone.

H5C6–N=NH5C6–N=N

N-hydroxy metabolite

–

OSO

–N=N

5C6

Sulfate conjugateHydroxyl amineAzoamino dye

Spontaneous

–

–SO

ionization

N Covalently bound adducts

DNA

RNA

–N=N H5C6–N=N

5C6

Resonance stabilized Nitrenium ion Highly reactive electrophilic metabolite

Fig. 6.37: N-oxidation of azoaminodye resulting in cellular toxicity.

N+CH

132 Komarla Kumarachari Rajasekhar*

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ferrous form of hemoglobin to the ferric form. This oxidized form of hemoglobin is called as “methemoglobin” or “ferrrihemoglobin”. Methemoglobin is unstable to transport oxygen and therefore leads to serious hypoxia and anemia [61]. N-oxidation of azoaminodyes like N-methyl-4-amino azo benzene (carcinogenic agent) (Fig.6.37) results in the formation of potentially reactive electrophilic metabolites. These metabolites bind covalently to cellular proteins, DNA and RNA [62].

N-oxidation of the nitrogen atoms present in aromatic heterocyclic moieties of

many drugs, for example trimethoprim (Fig.6.38), occurs to a minor extent [63].

H3CO

OCH

Trimethoprim

NNNH

Oxidation

1-N-Oxide metabolite

3-N-Oxide metabolite

Fig. 6.38: N-Oxidation in trimethoprim.

6.3.7.1.3 Oxidation of amides

Amide functionalities are susceptible to oxidative carbon-nitrogen bond cleavage (via α-carbon h

ydroxylation) and N-hydroxylation reactions. Oxidative dealkylation proceeds via an initially formed carbinolamide, which is unstable and fragments to form the N-dealkylated product. For example, diazepam (Fig.6.39) undergoes extensive N-demethylation to the pharmacologically active metabolite desmethyldiazepam [64].

hydroxylation

α carbon

N-dealkylation

Carbnolamide intermediate (Highly unstable)Diazepam

Desmethyl diazepam

Fig. 6.39: Oxidative dealkylation in diazepam.

6Drug metabolism 133

In the cyclic amides or lactams, hydroxylation of the alicyclic carbon α to the nitro- gen atom also leads to carbinolamides. An example of this pathway is the conversion of cotinine to 5-hydroxycotinine (Fig.6.40). This carbinolamide intermediate is in tautomeric equilibrium with the ring-opened metabolite γ-(3-pyridyl)-γ-oxo-Nmethylbutyramide [65]. N-Hydroxylation of aromatic amides, for example 2-acetylaminoflurene, may lead to the formation of chemically reactive intermediates. These intermediates are carcinogenic or cytotoxic in nature [66].

Cotinine

Fig. 6.40: Hydroxylation of alicyclic carbon α to the nitrogen.

5-hydroxy Cotinine Ring opened metabolite

6.3.7.2 Oxidation involving C-O bonds

Oxidative O-dealkylation of carbon-oxygen systems (mainly ethers) is catalyzed by microsomal mix

ed-function oxidases. This biotransformation involves an initial α-carbon hydroxylation to form either a hemiacetal or a hemiketal (Fig.6.41), which undergoes carbon-oxygen bond cleavage to yield the dealkylated oxygen species (phenol or alcohol) and a carbon moiety (aldehyde or ketone). Small alkyl groups (e.g., methyl or ethyl) attached to oxygen are O-dealkylated rapidly [67]. For example, morphine is the metabolic product of O-demethylation of codeine. Other drugs that undergo O-dealkylation are indomethacin, prazosin and metoprolol.

CRO

Hemiacetal or ketal

CRO

ROH

Phen ol or alcohol

Carbonyl compoundEther

Fig. 6.41: α-carbon hydroxylation in ethers.

In drugs that have several nonequivalent methoxy groups, one particular methoxy group is O-demethylated selectively or preferentially [68]. For example, 3, 4, 5-trimethoxy phenyl moiety in both mescaline and trimethoprim undergoes 3-O-demethylation preferentially (Fig.6.42).

134 Komarla Kumarachari Rajasekhar*

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H3CO

Mescaline

Fig. 6.42: O-demethylation in mescaline and trimethoprim.

2CH2NH2

H3CO

OCH

Trimethoprim

6.3.7.3 Oxidation involving C-S bonds

Carbon-sulfur functional groups are susceptible to S-dealkylation, desulfuration and S-o

xidation metabolic reactions. Both S-dealkylation and desulfuration involve oxidative cleavage of C-S bond. S-dealkylation is similar to N- and O-dealkylation and involves α-carbon hydroxylation [69]. For example, 6-(methylthio)purine is demethylated oxidatively to 6-mercaptopurine (Fig.6.43).

N H

6-mercaptopurine6-methylthiopurine

N H

+HCHO

Fig. 6.43: S-demethylation in methylthiopurine.

Oxidative conversion of C=S double bonds to corresponding C=O double bond is called desulfuration [70]. A well-known drug example of desulfuration is the conversion of thiopental to its corresponding oxygen analog pentobarbital (Fig.6.44). Desulfuration reaction also occurs with the P=S moiety (converted to P=O in the metabolite) present in several organophosphate insecticides, such as parathion [71, 72].

Organosulfur compounds commonly undergo S-oxidation to yield sulfoxide derivatives. Several phenothiazine derivatives are metabolized by this pathway. For example, both sulfur atoms present in thioridazine are susceptible to S-oxidation (Fig.6.45). Oxidation of the 2-methylthio group yields the active sulfoxide metabolite mesoridazine. Interestingly, mesoridazine is twice as potent an antipsychotic agent as thioridazine in humans [73, 74].

6Drug metabolism 135

N H

CH2CH2CH

2CH3

Thiopental

3CH2

Parathion (Organophosphate insecticide)

Desulfuration

N H

CH2CH2CH

2CH3

Pentobarbital

3CH2

Paraxon Active metabolite responsible for

Anti-choline esterase activity.

Fig. 6.44: Desulfuration of thiopental and parathion.

Thioridazine

S CH

Ring sulfoxide

Mesoridazine

(twice as potent as parent)

S CH

Ring sulfone

S CH

Sulforidazine

Fig. 6.45: S-oxidation in thioridazine.

S-oxidation is one of the important metabolic reactions in the H2-histamine antagonist cimetidine and metiamide. The corresponding sulfoxide derivatives are the major human urinary metabolites [75]. Sulfoxide drugs and metabolites may be further oxidized to sulfones (-SO

-). The sulfoxide group present in the immunosuppressive

agent oxisuran is metabolized to a sulfone moiety (Fig.6.46). Sulfoxide metabolites, such as those of thioridazine, reportedly undergo further oxidation to their sulfone derivatives [76].

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Oxisuran

Fig. 6.46: Oxidation of sulfoxide to sulfone in oxisuran.

Sulfone metabolite

6.3.7.3.1 Oxidation of alcohols and aldehydes

Many oxidative processes like benzylic, allylic, alicyclic, or aliphatic hydroxylation of corr

esponding drugs generate alcohol or carbinol metabolites as intermediate products. If not conjugated, these alcohol metabolites are further oxidized to aldehydes or ketones. Aldehyde metabolites resulting from oxidation of primary alcohols or from oxidative deamination of primary aliphatic amines undergo simple oxidation to generate polar carboxylic acid metabolites (Fig.6.47). Primary alcoholic and aldehyde functionalities are completely vulnerable to oxidation.

RCH2OH

NAD

+ NADH

RCHO

NAD

+ NADH

R COOH

Carboxylic acidAldehyde1° Alcohol

Fig. 6.47: Oxidation of alcohol and aldehyde to carboxylic acid.

Although secondary alcohols are susceptible to oxidation, this reaction is not often important because the reverse reaction, namely, reduction of the ketone back to the secondary alcohol, occurs quite readily. In addition, the secondary alcohol group, being polar and functionalized, is more likely to be conjugated than the ketone moiety (Fig.6.48).

Aliphatic Amines

Oxidative deamination

1o Alcohol If not conjugated Oxidation to Aldehydes

Alcohol If not conjugated Oxidation in to ketones

Reduction of Ketones

Fig. 6.48: Oxidation of primary and secondary alcohols.

further Oxidation

Carboxylic acid metabolites

6Drug metabolism 137

The bioconversion of alcohols to aldehydes and ketones is catalyzed by soluble alcohol dehydrogenases present in the liver and other tissues. NAD coenzyme, although NADP

also may serve as a coenzyme. The reaction catalyzed by

is required as a

alcohol dehydrogenase is reversible but often proceeds to the right because the aldehyde formed is further oxidized to the acid. Several aldehyde dehydrogenases, including aldehyde oxidase and xanthine oxidase, carry out the oxidation of aldehydes to their corresponding acids.

Soluble or microsomal dehydrogenase and oxidases are involved in oxidizing the carbinol group of the intermediate carbinolamine to a carbonyl moiety. For example, in the metabolism of medazepam to diazepam (Fig.6.49), the intermediate carbinolamine (2-hydroxymedazepam) undergoes oxidation of its 2-hydroxy group to a carbonyl moiety [77].

Diazepam

H3C

Medazepam

α carbon

hydroxylation

2-hydroxy medazepam (carbinolamine metabolite)

Oxidation

Fig. 6.49: Conversion of medazepam to diazepam.

6.3.7.3.2 Miscellaneous oxidative biotransformations

In addition to the many oxidative biotransformations discussed previously, oxidative aromatization or deh

ydrogenation and oxidative dehalogenation reactions also occur. Metabolic aromatization has been reported for norgestrel (Fig.6.50). Aromatization or dehydrogenation of the ring-A present in this steroid leads to the corresponding phenolic product 17α-ethinyl-18-homoestradiol as a minor metabolite in women [78].

Oxidative

AROMATIZATION

Norgestrel 17

Fig. 6.50: Metabolic aromatization of norgestrel.

-ethinyl-18-homo estradiol

138 Komarla Kumarachari Rajasekhar*

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Many halogen-containing drugs and xenobiotics are metabolized by oxidative dehalogenation. For example, the volatile anesthetic agent halothane is metabolized to trifluoroacetic acid [79]. It has been suggested that this metabolite arises from hydroxylation of halothane to form an initial carbinol intermediate that eliminates hydrogen bromide (dehalogenation) to yield trifluoroacetylchloride (Fig.6.51). The latter acyl chloride is chemically reactive and reacts rapidly with water to form trifluoroacetic acid. Alternatively, it can acylate tissue nucleophiles. Indeed, in vitro studies indicate that halothane is metabolized to a reactive intermediate (presumably trifluoroacetyl chloride), which covalently binds to liver microsomal proteins [80].

Hydroxylation

F3C

Halothane

Fig. 6.51: Metabolic hydroxylation of halothane.

Carbinol intermediate

Acylation Tissue nucleophiles

dehalogenation

– HBr

Triﬂuoro acetyl chloride

F3C

CF3COOH Triﬂuoro acetic acid

Covalently binds to

HCl

liver proteins Hepatotoxicity

Chloroform is metabolized oxidatively by a similar dehalogenation pathway to yield the chemically reactive species phosgene (Fig.6.52). Phosgene is responsible for the hepatotoxicity and nephrotoxicity associated with chloroform [81].

Chloroform

Carbinol intermediate

– HCl

Dehalogenation

Hepatotoxicity Nephrotoxicity

Phosgene

Covalently binds to liver proteins

+HCl

2CO3

Carbonic acid

Fig. 6.52: Metabolic dehalogenation of chloroform.

The dichloroacetamide portion of the antibiotic chloramphenicol undergoes oxidative dechlorination to yield a chemically reactive oxamyl chloride intermediate that can react with water to form the corresponding oxamic acid metabolite or can acylate microsomal proteins [82]. In several instances, oxidative dehalogenation can lead to the formation of toxic and reactive acyl halide intermediates (Fig.6.53).

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