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

Table 6–4
Indications and Unwanted Side Effects of Drug Metabolized by N-Acetyltransferases
DRUG INDICATION MAJOR SIDE EFFECTS
Acebutolol Arrhythmias, hypertension Drowsiness, weakness, insomnia
Amantadine Influenza A, parkinsonism Appetite loss, dizziness, headache, nightmares
Aminobenzoic acid Skin disorders, sunscreens Stomach upset, contact sensitization
Aminoglutethimide Adrenal cortex carcinoma, Clumsiness, nausea, dizziness, agranulocytosis
breast cancer
Aminosalicylic acid Ulcerative colitis Allergic fever, itching, leukopenia
Amonafide Prostate cancer Myelosuppression
Amrinone Advanced heart failure Thrombocytopenia, arrhythmias
Benzocaine Local anesthesia Dermatitis, itching, rash, methemoglobinemia
Caffeine Neonatal respiratory distress syndrome Dizziness, insomnia, tachycardia
Clonazepam Epilepsy Ataxia, dizziness, slurred speech
Dapsone Dermatitis, leprosy, AIDS-related complex Nausea, vomiting, hyperexcitability,
methemoglobinemia, dermatitis
Dipyrone, metamizole Analgesic Agranulocytosis
Hydralazine Hypertension Hypotension, tachycardia, flush, headache
Isoniazid Tuberculosis Peripheral neuritis, hepatotoxicity
Nitrazepam Insomnia Dizziness, somnolence
Phenelzine Depression CNS excitation, insomnia, orthostatic hypotension,
hepatotoxicity
Procainamide Ventricular tachyarrhythmia Hypotension, systemic lupus erythematosus
Sulfonamides Antibacterial agents Hypersensitivity, hemolytic anemia, fever,
lupus-like syndromes
For details, see Meisel, 2002.
known to be metabolized through acetylation, determining
an individual’s phenotype can be important in
maximizing outcome in subsequent therapy. For example,
hydralazine, a once popular orally active antihypertensive
(vasodilator) drug, is metabolized by NAT2; the
administration of therapeutic doses of hydralazine to a
slow acetylator can result in extreme hypotension and
tachycardia. Several drugs, such as the sulfonamides,
that are known targets for acetylation have been implicated
in idiosyncratic hypersensitivity reactions; in such
instances, an appreciation of a patient’s acetylating
phenotype is particularly important. Sulfonamides
are transformed into hydroxylamines that interact with
cellular proteins, generating haptens that can elicit
autoimmune responses. Individuals who are slow acetylators
are predisposed to drug-induced autoimmune
disorders.
Tissue-specific expression patterns of NAT1 and NAT2 have
a significant impact on the fate of drug metabolism and the potential
for eliciting a toxic episode. NAT1 is ubiquitously expressed among
most human tissues, whereas NAT2 is found predominantly in liver
and the GI tract. Both NAT1 and NAT2 can form N-hydroxy–
acetylated metabolites from bicyclic aromatic hydrocarbons, a reaction
that leads to the non-enzymatic release of the acetyl group and the
generation of highly reactive nitrenium ions. Thus, N-hydroxy acetylation
is thought to activate certain environmental toxicants. In contrast,
direct N-acetylation of bicyclic aromatic amines is stable and
leads to detoxification. Individuals who are NAT2 fast acetylators
are able to efficiently metabolize and detoxify bicyclic aromatic
amines through liver-dependent acetylation. Slow acetylators (NAT2
deficient), however, accumulate bicyclic aromatic amines, which
then become substrates for CYP-dependent N-oxidation. These N-
OH metabolites are eliminated in the urine. In tissues such as bladder
epithelium, NAT1 is highly expressed and can efficiently catalyze
the N-hydroxy acetylation of bicyclic aromatic amines, a process
that leads to de-acetylation and the formation of the mutagenic nitrenium
ion, especially in NAT2-deficient subjects. Epidemiological
studies have shown that slow acetylators are predisposed to bladder
cancer if exposed environmentally to bicyclic aromatic amines.
Methylation. In humans, drugs and xenobiotics can
undergo O-, N-, and S-methylation. The identification
of the individual methyltransferase (MT) is based on the
substrate and methyl conjugate. Humans express three
N-methyltransferases, one catechol-O-methyltransferase
(COMT), a phenol-O-methyltransferase (POMT), a
thiopurine S-methyltransferase (TPMT), and a thiol
methyltransferase (TMT). These MTs exist as
monomers and use S-adenosyl-methionine (SAM;