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

hyperbilirubinemia. Crigler-Najjar syndrome type I
is diagnosed as a complete lack of bilirubin
glucuronidation; Crigler-Najjar syndrome type II is differentiated
by the detection of low amounts of bilirubin
glucuronides in duodenal secretions. Types I and II
Crigler-Najjar syndrome are rare, and result from
genetic polymorphisms in the open reading frames of
the UGT1A1 gene, resulting in abolished or highly
diminished levels of functional protein.
Gilbert’s syndrome is a generally benign condition that is present
in up to 10% of the population; it is diagnosed clinically because circulating
bilirubin levels are 60-70% higher than those seen in normal
subjects. The most common genetic polymorphism associated with
Gilbert’s syndrome is a mutation in the UGT1A1 gene promoter, identified
as the UGT1A1*28 allele, which leads to reduced expression levels
of UGT1A1. Subjects diagnosed with Gilbert’s syndrome may be
predisposed to ADRs (Table 6-3) that result from a reduced capacity of
UGT1A1 to metabolize drugs. If a drug undergoes selective metabolism
by UGT1A1, competition for drug metabolism with bilirubin glucuronidation
will exist, resulting in pronounced hyperbilirubinemia as
well as reduced clearance of the metabolized drug. Tranilast [N-(3′4′-
demethoxycinnamoyl)-anthranilic acid] is an investigational drug used
for the prevention of restenosis in patients who have undergone transluminal
coronary revascularization (intracoronary stents). Tranilast
therapy in patients with Gilbert’s syndrome can to lead to hyperbilirubinemia,
as well as hepatic complications resulting from elevated levels
of tranilast.
Gilbert’s syndrome also alters patient responses to irinotecan.
Irinotecan, a prodrug used in chemotherapy of solid tumors
Table 6–3
Drug Toxicity and Gilbert’s Syndrome
PROBLEM
FEATURE
Gilbert’s syndrome UGT1A1*28 (main variant
in Caucasians)
Established toxicity reactions Irinotecan
Atazanavir
UGT1A1 substrates Gemfibrozil †
(potential risk?)
Ezetimibe
Simvastatin, atorvastatin,
cerivastatin †
Ethinylestradoil
Buprenorphine
Fulvestrant
Ibuprofen, ketoprofen
†
A severe drug reaction owing to the inhibition of glucuronidation
(UGT1A1) and CYP2C8 and CYP2C9 when both drugs were
combined led to the withdrawal of cerivastatin. Reproduced with
permission from Strassburg CP. Pharmacogenetics of Gilbert’s
syndrome. Pharmacogenomics, 2008, 9: 703–715. Copyright ©
2008 Future Medicine Ltd. All rights reserved.
(see Chapter 61), is metabolized to its active form, SN-38, by serum
carboxylesterases (Figure 6–5). SN-38, a potent topoisomerase
inhibitor, is inactivated by UGT1A1 and excreted in the bile
(Figures 6–7 and 6–8). Once in the lumen of the intestine, the SN-
38 glucuronide undergoes cleavage by bacterial β-glucuronidase and
reenters the circulation through intestinal absorption. Elevated levels
of SN-38 in the blood lead to bone marrow toxicities characterized
by leukopenia and neutropenia, as well as damage to the intestinal
epithelial cells (Figure 6–8), resulting in acute and life-threatening
diarrhea. Patients with Gilbert’s syndrome who are receiving irinotecan
therapy are predisposed to the hematological and GI toxicities
resulting from elevated serum levels of SN-38.
While most of the drugs that are metabolized by UGT1A1
compete for glucuronidation with bilirubin, Gilbert’s patients who
are HIV-positive and on protease inhibitor therapy with atazanavir
(REYATAZ) develop hyperbilirubinemia because the drug inhibits
UGT1A1 function. Although atazanavir is not a substrate for glucuronidation,
severe hyperbilirubinemia can develop in Gilbert’s
patients who have inactivating mutations in their UGT1A3 and
UGT1A7 genes. Clearly, drug-induced side effects attributed to the
inhibition of the UGT enzymes can be a significant concern and can
be complicated in the presence of gene inactivating polymorphisms.
The UGTs are expressed in a tissue-specific and often
inducible fashion in most human tissues, with the highest concentration
of enzymes found in the GI tract and liver. Based upon their
physicochemical properties, glucuronides are excreted by the kidneys
into the urine or through active transport processes through the
apical surface of the liver hepatocytes into the bile ducts where they
are transported to the duodenum for excretion with components of
the bile. Most of the bile acids that are conjugated are reabsorbed
from the gut back to the liver via enterohepatic recirculation; many
drugs that are glucuronidated and excreted in the bile can re-enter the
circulation by this same process. The β-D-glucopyranosiduronic
acids are targets for β-glucuronidase activity found in resident strains
of bacteria that are common in the lower GI tract, thus liberating the
free drug into the intestinal lumen. As water is reabsorbed into the
large intestine, the free drug can then be transported by passive diffusion
or through apical transporters back into the intestinal epithelial
cells, from which the drug can then re-enter the circulation.
Through portal venous return from the large intestine to the liver,
the reabsorption process allows for the reentry of drug into the systemic
circulation (Figures 3–7 and 3–8).
Sulfation. The sulfotransferases (SULTs) are
cytosolic and conjugate sulfate derived from
3′-phosphoadenosine-5′-phosphosulfate (PAPS) to the
hydroxyl and, less frequently, amine groups of aromatic
and aliphatic compounds. Like all of the xenobiotic metabolizing
enzymes, the SULTs metabolize a wide variety of
endogenous and exogenous substrates.
In humans, 13 SULT isoforms have been identified, and based
on sequence comparisons, have been classified into the SULT1
(SULT1A1, SULT1A2, SULT1A3/4, SULT1B1, SULT1C1, SULT1C2,
SULT1C4, SULT1E1), SULT2 (SULT2A1, SULT2B1a, SULT2B1b),
SULT4 (SULT4A1), and SULT6 (SULT6A1) families. SULTs play an
important role in normal human homeostasis. For example, SULT2B1b
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CHAPTER 6
DRUG METABOLISM