DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Table 17–2
Major Metabolic Relationships among Some of the Benzodiazepines a
N-DESALKYLATED
COMPOUNDS
3-HYDROXYLATED
COMPOUNDS
b
b
b
b
a
Compounds enclosed in boxes are marketed in the U.S. The approximate half-lives of the various compounds are denoted in parentheses; S (shortacting),
t 1/2
<6 hours; I (intermediate-acting), t 1/2
= 6-24 hours; L (long-acting), t 1/2
= >24 hours. All compounds except clorazepate are biologically
active; the activity of 3-hydroxydesalkylflurazepam has not been determined. Clonazepam (not shown) is an N-desalkyl compound, and it is metabolized
primarily by reduction of the 7-NO 2
group to the corresponding amine (inactive), followed by acetylation; its t 1/2
is 20-40 hours. † See text for
discussion of other pathways of metabolism.
rapidly, primarily by conjugation with glucuronic acid, such that
there is no appreciable accumulation of active metabolites. The fused
triazolo ring in estazolam lacks a methyl group and is hydroxylated
to only a limited extent; the major route of metabolism involves the
formation of the 3-hydroxyl derivative. The corresponding hydroxyl
derivatives of triazolam and alprazolam also are formed to a significant
extent. Compared with compounds without the triazolo ring,
the rate of this reaction for all three drugs is unusually swift, and the
3-hydroxyl compounds are rapidly conjugated or oxidized further to
benzophenone derivatives before excretion.
Midazolam is metabolized rapidly, primarily by hydroxylation
of the methyl group on the fused imidazo ring; only small
amounts of 3-hydroxyl compounds are formed. The α-hydroxylated
compound, which has appreciable biological activity, is eliminated
with a t 1/2
of 1 hour after conjugation with glucuronic acid. Variable
and sometimes substantial accumulation of this metabolite has been
noted during intravenous infusion (Oldenhof et al., 1988).
The aromatic rings (A and C) of the benzodiazepines are
hydroxylated only to a small extent. The only important metabolism
at these sites is reduction of the 7-nitro substituents of clonazepam,
nitrazepam, and flunitrazepam; the t 1/2
of these reactions are usually
20-40 hours. The resulting amines are inactive and are acetylated to
varying degrees before excretion.
Because the benzodiazepines apparently do not significantly
induce the synthesis of hepatic CYPs, their chronic administration
usually does not result in the accelerated metabolism of other substances
or of the benzodiazepines. Cimetidine and oral contraceptives
inhibit N-dealkylation and 3-hydroxylation of benzodiazepines.
Ethanol, isoniazid, and phenytoin are less effective in this regard.
These reactions usually are reduced to a greater extent in elderly