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

A
Fast
Slow
1557
3
B
Number of subjects
Cp (μg/ml)
2
1
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0
0.5
Slow
Fast
1.5 2.0 2.5 3.0 3.5 4.0
Elimination t 1/2 (hours)
0
0 5 10 15 20 25
Time (hours)
Figure 56–4. Multi-modal distribution of INH clearance due to NAT2 polymorphisms. Twenty-four male volunteers were given INH
(250 mg orally [3.3 ± 0.5 mg/kg; all subjects within 10% of estimated lean body mass]) and the time courses of plasma levels (C p
)
were assessed. (Modified with permission from Peloquin CA et al. Population pharmacokinetic modeling of isoniazid, rifampin, and
pyrazinamide. Antimicrob Agents Chemother; 1997, 41:2670. With permission from American Society for Microbiology.) A.
Frequency distribution of elimination half-times. Plotting elimination half-times (t 1/2
) as a frequency distribution demonstrates a group
of 8 subjects with t 1/2
values < 1.5 hours (mean = 1.2 hours), the fast acetylators, and a group of 16 with t 1/2
values > 2 hours (mean =
3.3 hours), the slow acetylators. B. Time course of plasma levels. The mean data (C p
vs time after administration) fall into two major
groups (see panel A). Both groups reached C Pmax
at 1 hour. One group (red line) achieved a higher C p
(3.6 μg/mL) with a mean elimination
t 1/2
= 3.3 hours (slow acetylators); the other group (green line) reached a lower maximal C p
(2.3 μg/mL) with a mean elimination
t 1/2
= 1.2 hours (fast acetylators).
Variation in expression of active and defective polymorphic forms of NAT2 characterize the fast and slow acetylators. Slow acetylators
may be a greater risk for adverse effects from INH, sulfonamides, and procainamide, whereas fast acetylators may have diminished
responses to standard doses of these agents but greater risk from bioactivation by NAT2 of arylamine/hydrazine carcinogens.
Recently, researchers have identified three elimination subgroups for INH metabolism, fast, slow, and intermediate (codominant fast
and slow alleles).
CHAPTER 56
CHEMOTHERAPY OF TUBERCULOSIS, MYCOBACTERIUM AVIUM COMPLEX DISEASE, AND LEPROSY
between 35 and 49 years and to 2.3% over 50 years of age. Overall
risk is increased by co-administration with rifampin to ~3%. Fatal
hepatitis is even rarer (0.02%). Most cases of hepatitis occur 4-8
weeks after the start of therapy.
If pyridoxine is not given concurrently, peripheral neuritis
(most commonly paresthesias of feet and hands) is encountered in
~2% of patients receiving isoniazid 5 mg/kg of the drug daily.
Neuropathy is more frequent in “slow” acetylators and in individuals
with diabetes mellitus, poor nutrition, or anemia. Other neurological
toxicities include convulsions in patients with seizure disorders,
optic neuritis and atrophy, muscle twitching, dizziness, ataxia, paresthesias,
stupor, and toxic encephalopathy. Mental abnormalities may