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

134
SECTION I
GENERAL PRINCIPLES
SN-38G
Intestinal
epithelial cells
COOH
H
H
OH
HO
H
SN-38
O
O
H
H
OH
HO
N
N
N
N
O
HO
O
HO
SN-38
HO
O
O
O
Bacterial
β-glucuronidase
Apical
transporter(s)
Basolateral
transporter(s)
O
N
SN-38
P-gp
UGT1A1
N
O
HO
O
Biliary excretion of
SN-38 glucuronide (SN-38G)
MRP2
SN-38G
O
MRP1
Apical side
(GI lumen)
Intestinal
epithelial cells
Basolateral side
(blood)
Figure 6–7. Routes of SN-38 transport and exposure to intestinal epithelial cells. SN-38 is transported into the bile following
glucuronidation by liver UGT1A1 and extrahepatic UGT1A7. Following cleavage of luminal SN-38 glucuronide (SN-38G) by bacterial
β-glucuronidase, reabsorption into epithelial cells can occur by passive diffusion (indicated by the dashed arrows entering the cell) as
well as by apical transporters. Movement into epithelial cells may also occur from the blood by basolateral transporters. Intestinal SN-
38 can efflux into the lumen through P-glycoprotein (P-gp) and multidrug resistance protein 2 (MRP2) and into the blood by means
of MRP1. Excessive accumulation of the SN-38 in intestinal epithelial cells and bone marrow, resulting from reduced glucuronidation,
can lead to the cellular damage and toxicity depicted in Figure 6-8 (Reproduced with permission from Tukey RH et al.
Pharmacogenetics of human UDP-glucuronosyltransferases and irinotecan toxicity. Mol Pharmacol, 2002, 62:446–450. Copyright ©
2002 The American Society for Pharmacology and Experimental Therapeutics.).
is a predominant form expressed in skin, carrying out the catalysis of
cholesterol. Cholesterol sulfate is an essential metabolite in regulating
keratinocyte differentiation and skin development. SULT2A1 is very
highly expressed in the fetal adrenal gland, where it produces the
large quantities of dehydroepiandrosterone sulfate that are required for
placental estrogen biosynthesis during the second half of pregnancy.
SULT1A3 is highly selective for catecholamines, while estrogens (in
particular 17β-estradiol) are sulfated by SULT1E1. In humans, significant
BLOOD AND TISSUES
(basolateral)
GI
EPITHELIUM
GI LUMEN
(apical)
Leukopenia
Neutropenia
Toxicity
Blood Cells
CPT-11
Carboxylesterase
SN-38
UGT1A1
UGT1A7
SN-38G
(bile)
β-glucuronidase
SN-38G
(fecal excretion)
SN-38
SN-38
Toxicity
Diarrhea
Figure 6–8. Cellular targets of SN-38 in the blood and intestinal tissues. Excessive accumulation of SN-38 can lead to bone marrow
toxicities such as leukopenia and neutropenia, as well as damage to the intestinal epithelium. These toxicities are pronounced in
individuals that have reduced capacity to form the SN-38 glucuronide, such as patients with Gilbert’s syndrome. Note the different
body compartments and cell types involved (Reproduced with permission from Tukey RH et al. Pharmacogenetics of human UDPglucuronosyltransferases
and irinotecan toxicity. Mol Pharmacol, 2002, 62:446–450. Copyright © 2002 The American Society for
Pharmacology and Experimental Therapeutics.)