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

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N
N
CONH 2
CYP
O
N
O O O
N
N
CHAPTER 6
CH 2 CH 3
H 3 C
HO
N
CONH 2
mEH
OH
N N C O HO
Irinotecan
H 2 O
CES2
CH 2 CH 3
N
O
OH O
O
DRUG METABOLISM
N
N
CONH 2
Figure 6–4. Metabolism of carbamazepine by CYP and microsomal
epoxide hydrolase (mEH). Carbamazepine is oxidized to the
pharmacologically-active metabolite carbamazepine-10,
11-epoxide by CYP. The epoxide is converted to a transdihydrodiol
by mEH. This metabolite is biologically inactive and
can be conjugated by phase 2 enzymes.
The carboxylesterases comprise a superfamily of
enzymes that catalyze the hydrolysis of ester- and
amide-containing chemicals. These enzymes are found
in both the endoplasmic reticulum and the cytosol of
many cell types and are involved in detoxification or
metabolic activation of various drugs, environmental
toxicants, and carcinogens. Carboxylesterases also
catalyze the activation of prodrugs to their respective
free acids. For example, the prodrug and cancer
chemotherapeutic agent irinotecan is a camptothecin
analog that is bioactivated by plasma and intracellular
carboxylesterases to SN-38 (Figure 6–5), a potent
inhibitor of topoisomerase 1.
CONJUGATING ENZYMES
(PHASE 2 REACTIONS)
There are a large number of phase 2 conjugating
enzymes, all of which are considered to be synthetic in
nature since they result in the formation of a metabolite
with an increased molecular mass. Phase 2 reactions
also normally terminate the biological activity of the
drug, although for drugs like morphine and minoxidil,
glucuronide and sulfate conjugates, respectively, are
UDP-glucuronic
acid
COOH
O
OH
HO O
OH
SN-38
more pharmacologically active than the parent. The
contributions of different phase 2 reactions to drug
metabolism are shown in Figure 6–3B. Two of the
phase 2 reactions, glucuronidation and sulfation, result
in the formation of metabolites with a significantly
increased water-to-lipid partition coefficient, resulting
in hydrophilicity and facilitating metabolite accumulation
in the aqueous compartments of the cell and the
body. While sulfation and acetylation terminate the biological
activity of drugs, the solubility properties of
these metabolites are altered through minor changes in
the overall charge of the molecule. Characteristic of the
phase 2 reactions is the dependency on the catalytic
N
UGT1A1/7
UDP
CH 2 CH 3
SN-38 glucuronide
H 3 C OH O
H 3 C OH O
Figure 6–5. Metabolism of irinotecan (CPT-11). The pro-drug
CPT-11 is initially metabolized by a serum esterase (CES2) to
the topoisomerase inhibitor SN-38, which is the active
camptothecin analog that slows tumor growth. SN-38 is then
subject to glucuronidation, which results in loss of biological
activity and facilitates elimination of the SN-38 in the bile.
N
O
O
O