used quite commonly). While cyclopropane may be reactive, due to ring strain,
cyclopentane and cyclohexane are metabolically inert. These substituents are useful for
increasing lipid solubility.
Alkenes.Alkenes are, in general, metabolically stable. The majority of alkene-
containing drugs do not exhibit significant rapid metabolism at the double bond. There
are some isolated examples of alkene-containing compounds that undergo epoxidation,
catalyzed by mixed-function oxidase, or that add water across the double bond to give
an alcohol.
Halogenated Hydrocarbons.Halogenated hydrocarbons are not easily metabolized
and show significant stability in vivo. The addition of halogens tends to increase the
lipophilicity and to prolong the half-life of the drug.
Aromatic Hydrocarbons.Aromatic rings are very susceptible to oxidation, in par-
ticular to aromatic hydroxylation. The oxidation of aromatic rings frequently proceeds
via an epoxide intermediate, which may actually be stable enough to be isolated. The
hydroxylation of an aromatic ring increases hydrophilicity, thus promoting renal excre-
tion and slightly decreasing the half-life of the drug. Aromatic hydrocarbons are oxi-
dized in a number of organs, but the liver is a preferred location.
Alcohols.The alcohol functional group tends to be metabolized by a variety of
enzymes. Primary and secondary alcohols are oxidized to carboxylic acids or ketones.
Tertiary alcohols are substantially more stable to oxidation. Rather than oxidase-mediated
oxidation, alcohols can also be conjugated. If the alcohol is conjugated with glucuronic
acid, a glucuronide forms; if it is conjugated with sulfuric acid, a sulfate is formed.
Regardless, both of these conjugations increase hydrophilicity and decrease the half-life
of the drug molecule.
Phenols.Phenols are oxidized via hydroxylation to yield a diphenolic molecule.
This hydroxylation is either orthoorparato the primary alcohol. Phenols may also be
conjugated with either glucuronic acid or sulfuric acid.
Ethers.In general, ethers are very stable and are excreted unchanged. Sometimes,
an ether that involves a small alkyl group (occasionally a methyl, rarely an ethyl) will be
dealkylated, with the small alkyl group being excreted as an aldehyde; the remainder of
the drug molecule is left as an alcohol.
150 MEDICINAL CHEMISTRY
Figure 3.8 Metabolism of butylbarbital by mixed-function oxidase.