-Acetyltransferase 2 Genotypes among Zulu-Speaking South Africans and Isoniazid and -Acetyl-Isoniazid Pharmacokinetics during Antituberculosis Treatment.

Journal:
Antimicrobial agents and chemotherapy, Volume: 64, Issue: 4
Published:
March 24, 2020
PMID:
31964788
Authors:
Thuli Mthiyane T, James Millard J, John Adamson J, Yusentha Balakrishna Y, Cathy Connolly C, Andrew Owen A, Roxana Rustomjee R, Keertan Dheda K, Helen McIlleron H, Alexander S Pym AS
Abstract:

The distribution of -acetyltransferase 2 gene () polymorphisms varies considerably among different ethnic groups. Information on single-nucleotide polymorphisms in the South African population is limited. We investigated polymorphisms and their effect on isoniazid pharmacokinetics (PK) in Zulu black HIV-infected South Africans in Durban, South Africa. HIV-infected participants with culture-confirmed pulmonary tuberculosis (TB) were enrolled from two unrelated studies. Participants with culture-confirmed pulmonary TB were genotyped for the polymorphisms 282C>T, 341T>C, 481C>T, 857G>A, 590G>A, and 803A>G using Life Technologies prevalidated TaqMan assays (Life Technologies, Paisley, UK). Participants underwent sampling for determination of plasma isoniazid and -acetyl-isoniazid concentrations. Among the 120 patients, 63/120 (52.5%) were slow metabolizers (), 43/120 (35.8%) had an intermediate metabolism genotype (), and 12/120 (11.7%) had a rapid metabolism genotype (, , and ). The alleles evaluated in this study were , , , , , , , , , , and was the most frequent allele (70.4%), followed by (27.9%). Fifty-eight of 60 participants in study 1 had PK results. The median area under the concentration-time curve from 0 to infinity (AUC) was 5.53 (interquartile range [IQR], 3.63 to 9.12 μg h/ml), and the maximum concentration ( ) was 1.47 μg/ml (IQR, 1.14 to 1.89 μg/ml). Thirty-four of 40 participants in study 2 had both PK results and genotyping results. The median AUC was 10.76 μg·h/ml (IQR, 8.24 to 28.96 μg·h/ml), and the was 3.14 μg/ml (IQR, 2.39 to 4.34 μg/ml). Individual polymorphisms were not equally distributed, with some being represented in small numbers. The genotype did not correlate with the phenotype, with those with a rapid acetylator genotype showing higher AUC values than those with a slow acetylator genotype, but the difference was not significant ( = 0.43). There was a high prevalence of slow acetylator genotypes, followed by intermediate and then rapid acetylator genotypes. The poor concordance between genotype and phenotype suggests that other factors or genetic loci influence isoniazid metabolism, and these warrant further investigation in this population.