C h a p t e r 3 0
Disorders of Hepatobiliary and Exocrine Pancreas Function
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These reactions, often referred to as
biotransformations,
are important considerations in drug therapy.
Phase 1 reactions
result in the chemical modification
of reactive drug groups through oxidation, reduction,
hydroxylation, or other chemical reactions. Many of
these reactions involve drug-metabolizing enzymes that
are located in the lipophilic endoplasmic reticulummem-
branes of liver cells. One of the enzymes involved is the
product of a gene superfamily called
cytochrome P450
(abbreviated CYP or CYP P450). Multiple isoforms of
the CYP enzyme have been identified and traced to the
metabolism of specific drugs and to potential interac-
tions among drugs. Of these isoforms, the CYP3A4
enzyme accounts for approximately 50% of the liver’s
drug-metabolizing activity.
23
Many gene members of the
CYP
enzyme system
can have their activity induced or suppressed as they
undergo the task of metabolizing drugs. For example,
drugs such as alcohol and barbiturates can induce cer-
tain members to increase enzyme production, accelerat-
ing drug metabolism and decreasing the pharmacologic
action of the drug and of coadministered drugs that
use the same member of the CYP system. In the case of
drugs metabolically transformed to reactive intermedi-
ates, enzyme induction may exacerbate drug-mediated
tissue toxicity. Certain drugs can also inhibit enzymes in
the CYP system. For example, the antibiotic erythromy-
cin and the antifungal agents fluconazole, itraconazole,
and ketoconazole inhibit CYP3A4 enzyme activity, as
does grapefruit juice, thereby decreasing the metabolism
of drugs that use this enzyme system.
23
Phase 2 reactions,
which involve the conversion of
lipid-soluble derivatives to water-soluble substances
called
conjugates
, may follow phase 1 reactions or pro-
ceed independently. Conjugation, a process that couples
the drug with an activated endogenous compound such
as glutathione, renders the drug more water soluble so
it can be excreted in the bile or urine. Although many
water-soluble drugs and endogenous substances are
excreted unchanged in the urine or bile, lipid-soluble
substances tend to accumulate in the body unless they
are converted to less active compounds or water-soluble
metabolites. Because the endogenous substrates used
in the conjugation process are obtained from the diet,
nutrition plays a critical role in phase 2 reactions.
In addition to its role in metabolism of drugs and
chemicals, the liver also is responsible for hormone inac-
tivation or modification. Insulin and glucagon are inac-
tivated by proteolysis or deamination. Thyroxine and
triiodothyronine are metabolized by reactions involving
deiodination. Steroid hormones such as the glucocorti-
coids are first inactivated by a phase 1 reaction and then
conjugated by phase 2 reactions.
Drug-Induced Liver Disease
Many widely used therapeutic drugs, including over-
the-counter medications and “natural” products,
can cause hepatic injury.
23
Hepatotoxicity is the lead-
ing cause of acute liver failure in the United States.
The drug most commonly involved is acetaminophen,
with half the cases reported to be unintentional over-
doses.
24
Unintentional overdoses may occur when people
unknowingly take several over-the-counter preparations
that contain acetaminophen (e.g., an acetaminophen-
containing cold preparation and acetaminophen pain
medication). Numerous host factors contribute to the
susceptibility to drug-induced liver disease, including
genetic predisposition, age, underlying chronic liver dis-
ease, diet and alcohol consumption, and the use of mul-
tiple interacting drugs.
Drugs and chemicals can exert their effects by caus-
ing hepatocyte injury and death or by cholestatic liver
damage due to injury of biliary drainage structures.
Drug reactions can be acute or chronic, and predictable
based on the drug’s chemical structure and metabolites
or unpredictable (idiosyncratic) based on individual
characteristics of the person receiving the drug.
Direct Predictable Injury.
Some drugs are known to
have toxic effects on the liver. Examples are acetamino-
phen, isoniazid, and phenytoin. Direct hepatic damage,
which is often age and dose dependent, usually results
from drug metabolism and the generation of toxic
metabolites. Because of the greater activity of the drug-
metabolizing enzymes in the central zones of the liver,
these agents typically cause centrilobular necrosis. The
injury is characterized by marked elevations in ALT and
AST values with minimally elevated ALP. Bilirubin lev-
els invariably are increased, and the prognosis often is
worse when hepatocellular necrosis is accompanied by
jaundice.
Idiosyncratic Reactions.
In contrast to direct pre-
dictable drug reactions, idiosyncratic reactions are
unpredictable, not related to dose, and sometimes
accompanied by features suggesting an allergic reaction.
Drugs are relatively small molecules and, therefore,
unlikely to provoke an immune response. However, in
the process of biotransformation, drugs may combine
with enzymes, producing a compound large enough to
serve as an antigen and induce the formation of anti-
bodies or a direct cytotoxic T-cell response. In some
cases, the reaction results directly from a metabolite
that is produced only in certain persons based on a
genetic predisposition. For example, certain people are
capable of rapid acetylation of isoniazid, an antituber-
culosis drug.
Cholestatic Reactions.
Cholestatic drug reactions
result in decreased secretion of bile or obstruction of
the biliary tree. Acute intrahepatic cholestasis is one of
the most frequent types of idiosyncratic drug reactions.
Among the drugs credited with causing cholestatic
drug reactions are estradiol; chlorpromazine, an anti-
psychotic drug; and some of the antibiotics, including
amoxicillin/clavulanic acid, erythromycin, and nafcillin.
Typically, cholestatic drug reactions are characterized by
an early onset of jaundice and pruritus, with little altera-
tion in the person’s general feeling of well-being. Most
instances of acute drug-induced cholestasis subside once
the drug is withdrawn.
