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

1556 Other products of KatG activation of INH include superoxide,
H 2
O 2
, alkyl hydroperoxides, and the NO radical, which may also
contribute to the mycobactericidal effects of INH (Timmins and
Deretic, 2006). M. tuberculosis could be especially sensitive to
damage from these radicals because the bacilli have a defect in the
central regulator of the oxidative stress response, oxyR. Backup
defense against radicals is provided by alkyl hydroperoxide reductase
(encoded by ahpC), which detoxifies organic peroxides.
Increased expression of ahpC reduces isoniazid effectiveness.
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
Antibacterial Activity. The isoniazid MICs with clinical M. tuberculosis
strains vary from country to country. In the U.S., e.g., the MICs are
0.025-0.05 mg/L (Heifets, 1991). Activity against M. bovis and M.
kansasii is moderate. Isoniazid has poor activity against MAC. It has
no activity against any other microbial genus.
Mechanisms of Resistance. The prevalence of drug-resistant
mutants is ~1 in 10 6 bacilli. Because TB cavities may contain as
many as 10 7 to 10 9 microorganisms, preexistent resistance can be
expected in pulmonary TB cavities of untreated patients. These spontaneous
mutants can be selected by monotherapy; indeed, strains
resistant to isoniazid will be selected and amplified by isoniazid
monotherapy. Thus two or more agents are usually used. Because
the mutations resulting in drug resistance are independent events,
the probability of resistance to two antimycobacterial agents is small,
~1 in 10 12 (1 × 10 6 × 10 6 ), a low probability considering the number
of bacilli involved.
Resistance to INH is associated with mutation or deletion of
katG, overexpression of the genes for inhA (confers low-level resistance
to INH and some cross-resistance to ethionamide), and ahpC
and mutations in the kasA and katG genes. KatG mutants exhibit a
high level of resistance to isoniazid (Zhang and Yew, 2009). The
most common mechanism of isoniazid resistance in clinical isolates
is due to single point mutations in the heme binding catalytic domain
of KatG, especially a serine to asparagine change at position 315.
Although isolates with this mutation completely lose the ability to
form nicotinoyl-NAD + /NADP + adducts, they retain good catalase
activity and maintain good biofitness. Compensatory mutations in
the ahpC promoter occur and increase survival of katG mutant
strains under oxidative stress.
KatG 315 mutants have a high probability of co-occurrence
with ethambutol resistance (Hazbón et al., 2006; Parsons et al.,
2005). Mutations in katG, ahpC, and inhA have also been associated
with rpoB mutations (Hazbón et al., 2006). This suggests that
mutations at different loci associated with resistance to different
drugs may somehow interact to make multiple drug resistance
more likely. In the laboratory, efflux pump induction by isoniazid
has been demonstrated, and it also confers resistance to ethambutol
(Colangeli et al., 2005). In an in vitro pharmacodynamic
model, efflux pump-induced resistance developed within 3 days
and was followed by development of katG mutations (Gumbo
et al., 2007b).
Absorption, Distribution, and Excretion. The bioavailability of orally
administered isoniazid is ~100% for the 300 mg dose. The pharmacokinetics
of isoniazid are best described by a one-compartment model,
with the pharmacokinetic parameters in Table 56–2 (Kinzig-Schippers
et al., 2005). The ratio of isoniazid in the epithelial lining fluid to that
in plasma is 1-2 and for CSF is 0.9 (Conte et al., 2002). Approximately
10% of drug is bound to protein. From 75-95% of a dose of isoniazid
is excreted in the urine within 24 hours, mostly as acetylisoniazid and
isonicotinic acid.
Isoniazid is metabolized by hepatic arylamine N-acetyltransferase
type 2 (NAT2), encoded by a variety of NAT2* alleles (Figure
56–3). The drug is N-acetylated to N-acetylisoniazid in a reaction
that uses acetyl-coA. Isoniazid clearance in patients has been traditionally
classified as one of two phenotypic groups: “slow” and
“fast” acetylators, as seen in Figure 56–4. Recently, the phenotypic
groups have been expanded to fast, intermediate, and slow acetylators,
and population pharmacokinetic parameters of isoniazid have
been estimated and related to NAT2 genotype; the number of
NAT2*4 alleles account for 88% of the variability of INH clearance
(Kinzig-Schippers et al., 2005).
The frequency of each acetylation phenotype depends on race
but is not influenced by sex or age. Fast acetylation is found in Inuit
and Japanese. Slow acetylation is the predominant phenotype in
most Scandinavians, Jews, and North African whites. The incidence
of “slow acetylators” among various racial types in the U.S. is ~50%.
Because high acetyltransferase activity (fast acetylation) is inherited
as an autosomal dominant trait, “fast acetylators” of isoniazid are
either heterozygous or homozygous. Although it has been useful to
categorize different “racial” groups dominated by one or the other of
these phenotypes, the more precise approach will be to determine
the NAT2*4 alleles for each patient to guide therapy for that patient
in the future.
Microbial Pharmacokinetics-Pharmacodynamics. Isoniazid’s
microbial kill is best explained by the AUC 0-24
-to-MIC ratio (Gumbo
et al., 2007c). Resistance emergence is closely related to both
AUC/MIC and C max
/MIC (Gumbo et al., 2007c). Because AUC is
proportional to dose/CL, this means that efficacy is most dependent
on drug dose and CL, and thus on the activity of NAT-2 polymorphic
forms. This also suggests that dividing the isoniazid dose into
more frequent doses may be detrimental in terms of resistance emergence,
and more intermittent dosing would be better (Chapter 48).
Therapeutic Uses. Isoniazid is available as a pill, as an elixir,
and for parenteral administration. The commonly used total daily
dose of isoniazid is 5 mg/kg, with a maximum of 300 mg; oral
and intramuscular doses are identical. Children should receive
10-15 mg/kg/day (300 mg maximum). Dosing information in the
treatment of M. tuberculosis and M. kansasii infections is given
in section II and VI.
Untoward Effects. After NAT2 converts isoniazid to acetylisoniazid,
which is excreted by the kidney; acetylisoniazid can also be
converted to acetylhydrazine (Roy et al., 2008), and then to hepatotoxic
metabolites by CYP2E1. Alternatively, acetylhydrazine may
be further acetylated by NAT-2 to diacetylhydrazine, which is nontoxic.
In this scenario, rapid acetylators will rapidly remove acetylhydrazine
while slower acetylators or induction of CYP2E1 will lead
to more toxic metabolites. Rifampin is a potent inducer of CYP2E1,
which is why it potentiates isoniazid hepatotoxicity.
Elevated serum aspartate and alanine transaminases are
encountered commonly in patients on isoniazid. However, the
enzyme levels often normalize even when isoniazid therapy is continued
(Blumberg et al., 2003). Severe hepatic injury occurs in
~0.1% of all patients taking the drug. Hepatic damage is rare in
patients <20 years old but the incidence increases with age to 1.2%