Figures & data
Table 1. NAT2 SNPs and their corresponding alleles/haplotypesa
Figure 1. INH pharmacokinetics in subjects with rapid, intermediate, and slow NAT2 acetylator genotype
Each bar represents mean ± SEM for the INH plasma half-life (a) or the area under the concentration–time curve (b) following a single oral dose of 5 or 10 mg/kg INH in individuals with homozygous rapid acetylator genotype (black), heterozygous acetylator genotype (gray) or homozygous slow acetylator genotype (white). Differences among the NAT2 genotypes were highly significant (p < 0.0001). Modified from [Citation14,Citation32]. (c) INH clearance values subjects with rapid, intermediate, or slow acetylator NAT2 genotypes. Each bar represents Mean ± SD. Adapted from [Citation33]. (d) INH N-acetylation metabolic ratios in subjects with defined NAT2 acetylator genotypes. Bars illustrate mean and range of ratios obtained in 70 total patients. Modified from [Citation34]. (e) INH N-acetylation in cryopreserved human hepatocytes from individuals with rapid, intermediate, and slow NAT2 acetylator genotype. Bars illustrate mean ± SEM acetyl-INH levels in five rapid, intermediate and slow acetylators incubated with 12.5 or 100 µM INH. The levels of acetyl-INH differed significantly between the acetylator genotypes following incubation with 12.5 µM (p = 0.0023) or 100 µM (p = 0.0002) INH. Modified from [Citation28].
Figure 2. HYD N-acetyltransferase activities in vitro in cryopreserved human hepatocytes from rapid, intermediate and slow NAT2 acetylators
Bars illustrate Mean ± SEM for HYD N-acetyltransferase activities from rapid (n = 6), intermediate (n = 5), and slow (n = 5) NAT2 acetylators at 100 (a) or 10 (b) µM. HYD N-acetyltransferase activities differed significantly with respect to NAT2 phenotype at each concentration tested: 100 µM (p = 0.002); and 10 µM hydralazine (p = 0.0029). HYD N-Acetylation in situ in cryopreserved human hepatocytes from rapid, intermediate and slow acetylators. Bars illustrate Mean ± SEM HYD N-acetylation rates in rapid (solid bar; n = 5), intermediate (gray bar; n = 5) and slow (white bar; n = 5) acetylators following incubation with 100 (c) or 10 (d) µM HYD. N-acetylation rates differed significantly among the rapid, intermediate and slow acetylators at 10 µM (p = 0.002) and 100 µM (p = 0.0015) HYD. (e) HYD N-acetylation in vitro in cryopreserved human hepatocytes among slow NAT2 acetylator genotypes. Bars illustrate Mean ± SEM HYD N-acetylation rates in NAT2*5B/*5B (n=5), NAT2*5B/*6A (n=6), and NAT2*6A/*6A (n=5) genotypes. HYD N-acetyltransferase activities differed significantly with respect to slow acetylator NAT2 genotype (p<0.001). Modified from [Citation54].
Figure 3. (a) SMZ N-acetyltransferase catalytic activities in cryopreserved human hepatocyte samples
Bars illustrate mean ± SEM in rapid acetylator genotypes (black; n = 18), intermediate acetylator genotypes (gray; n = 114) and slow acetylator genotypes (white; n = 124). SMZ N-acetyltransferase activities differed significantly (p < 0.0001) with respect to NAT2 acetylator genotype. Modified from [Citation57]. (b) SMZ N-acetyltransferase catalytic activities (mean ± SEM) in cryopreserved human hepatocytes are plotted on the ordinate versus NAT2 genotype(s) on the abscissa. The black bar illustrates rapid acetylator genotypes, gray bars illustrate intermediate acetylator genotypes and white bars illustrate slow acetylator genotypes. Modified from [Citation21]. (c) SMZ N-acetylation in cryopreserved human hepatocytes. Each bar illustrates mean ± SEM from rapid (n = 6) intermediate (n = 6) and slow (n = 9) acetylators. Modified from [Citation58]. (d) Percent acetyl-SMZ to SMZ ratios in plasma of healthy subjects from China [Citation56] and from healthy and cancer patients from Mexico [Citation55]. Each bar represents Mean ± SEM for individuals with rapid (n = 53 or 18), intermediate (n = 47 or 47) or slow (n = 20 or 57) NAT2 acetylator genotypes. (e) SMZ N-acetylation in human cryopreserved human hepatocytes from subjects with NAT2*5B/*5B (black), NAT2*5B/*6A (gray) or NAT2*6A/*6A (white) acetylator genotypes. Each bar illustrates mean ± SEM for NAT2*5B/*5B (n = 10), NAT2*5B/*6A (n = 9), and NAT2*6A/*6A (n = 7) individual human hepatocyte samples. Differences in N-acetylation differed significantly at both 10 and 200 µM (p = 0.0144 and p = 0.0024) respectively. Modified from [Citation59].
Figure 4. Estimated frequency of treatment failure and toxicity of INH treatment for tuberculosis in populations across the world
Adapted from [Citation89].
Table 2. Amifampridine pharmacokinetic parameters in rapid and slow NAT2 acetylators