N‐acetylation polymorphism of dapsone in a Japanese population.

Abstract

1 The N-acetylation of dapsone (DDS) was studied in 182 unrelated healthy Japanese subjects. The frequency of slow acetylators determined using the plasma monoacetyldapsone (MADDS) to DDS ratio (MADDS/DDS, slow acetylators < 0.30 and rapid acetylators > 0.35) at 3 h after an oral dose of DDS (100 mg) was 6.6% (12 of the 182 subjects) with a 95% confidence interval of 3.8 to 11.2%. 2 The frequency distribution histogram of the plasma MADDS/DDS ratio showed an apparent trimodal pattern. However, the numbers of heterozygous (n = 105) and homozygous rapid acetylators (n = 65) derived from the observed data did not agree with those predicted for the respective rapid acetylators (n = 70, and n = 100) by applying the Hardy-Weinberg Law, when the suggested antimode of 0.85 discriminating these two rapid acetylators was employed. 3 The incidence of slow acetylators was unexpectedly lower in the males (1.4%, 1 of the 69 subjects, with a 95% confidence interval of 0.2 to 7.7%) compared with the incidence in the females (9.7%, 11 of the 113 subjects, with a 95% confidence interval of 5.5 to 16.6%). The difference reached a marginally significant level (Fisher's exact probability test, P = 0.02). 4 The mean plasma concentration of MADDS was significantly (P < 0.001) lower in the slow compared to the rapid acetylators and there was a highly significant correlation (rs = 0.757, P < 0.001) between plasma MADDS levels and MADDS/DDS ratios. 5 Slow acetylators showed a significantly (P < 0.001) lower urinary MADDS/DDS ratio and excreted less (P < 0.001) MADDS than rapid acetylators. Although there was a highly significant relationship (r, = 0.612, P < 0.001) between plasma and urinary acetylation ratios, the latter was not in complete concordance with the phenotyping derived from the plasma acetylation ratios. Therefore, measurement of a urinary acetylation ratio (MADDS/ DDS) was confirmed not to be a non-invasive phenotyping method.

A population phenotyping study of three drug‐metabolizing enzymes in Kyushu, Japan, with use of the caffeine test

“…18 The frequencies of slow acetylators are known to show large interethnic differences (eg, 90% in North Africans, 40% to 60% in white subjects, 16% to 26% in Chinese subjects, and 6% to 15% in Japanese subjects). 18,[34][35][36][37][38][39][40] In Japan, there are local or intraethnic differences in the frequency of slow acetylators, and slow acetylator frequencies in the southern and northern areas of Kyushu have been reported to be 9.2% and 13.9%, respectively. 34 The frequency of slow acetylators observed in our study (11.0%) was fairly compatible with this previous report.…”

“…A previous study in a Japanese population with dapsone as a probe drug also showed a trimodal distribution that did not fit with the distribution expected by application of the Hardy-Weinberg theory. 35 We are tempted to assume that NAT2 activity may be inhibited by unknown genetic or environmental factors in rapid and intermediate acetylators in Japanese.…”

Risk factors for antituberculous chemotherapy‐induced hepatotoxicity in Japanese pediatric patients

“…21 Finally, because we did not determine the phenotypes or genotypes of N-acetyltransferase 2 in the children in our study, we cannot address whether slow acetylator status might have been an independent risk factor for hepatotoxicity in children. Because the majority of Japanese subjects (ie, Ͼ90%) are rapid acetylators, 22 a far greater number of patients will be required to determine whether N-acetylation status would be an independent risk factor for hepatotoxicity associated with antituberculosis chemotherapy, unless it is an extremely strong risk factor.…”

Simultaneous High Performance Liquid Chromatographic Determination of Dapsone and Monoacetyldapsone in Human Plasma and Urine

“…It undergoes metabolism by acetylation which exhibits a genetically controlled bimodal distribution within a given population (4). Assignment of acetylator phenotype, rapid or slow, can be done by monitoring the plasma concentration ratio of MAD to D D S (5)(6). This emphasizes the importance of devising a sensitive and specific method for the determination of D D S and MAD in biological fluids.…”