N-acetyltransferase 2 genotypes amongst ulu Speaking South Africans and isoniazid / N-acetyl-isoniazid pharmacokinetics during ant-tuberculosis treatment

Background: Distribution of N-acetyltransferase2 (NAT2) polymorphisms varies considerably among different ethnic groups. Information is limited on NAT2 single nucleotide polymorphisms in the South African population. We investigated NAT2 polymorphisms and their effect on isoniazid pharmacokinetics in Zulu black HIV-infected South Africans in Durban, South Africa. Methods: HIV-infected participants, with culture-confirmed pulmonary tuberculosis (TB) were enrolled from two unrelated studies. Culture-confirmed participants were genotyped for NAT2 polymorphisms 282C>T, 341T>C, 481C>T, 857G>A, 590G>A and 803A>G using Life Technologies pre-validated Taqman assays (Life Technologies, Paisley, UK). Participants underwent sampling for plasma isoniazid and N-acetylisoniazid concentrations. Results: Amongst the 120 patients, 63/120 (52.5%) were slow metabolisers (NAT2*5/*5), 43/120 (35.8%) intermediate (NAT2*5/12), and 12/120 (11.7%) rapid metabolisers (NAT2*4/*11, NAT2*11/12 and NAT2*12/12). NAT2 alleles in this study were *4, *5C, *5D, *5E, *5J, *5K, *5KA, *5T, *11A, *12A/12C and *12M. NAT2*5 was the most frequent allele (70.4%) followed by NAT2*12 (27.9%). 34/40 had both PK results and NAT2 genotyping results. The median area under the concentration-time-curve to infinity (AUC0-∞) interquartile range (IQR) was 7.81 (5.87 - 16.83) µg/ml/hr and maximum concentration (Cmax) 3.14 µg/ml (2.42 - 4.36) µg/mL. Individual polymorphisms were not equally distributed, with some represented in small numbers. Genotype did not correlate with phenotype, rapid genotype showing higher AUC0-∞ than slow but not significant, p=0.43. Conclusion: There was a high prevalence of slow followed by intermediate then rapid acetylator genotypes. The poor concordance between genotype and phenotype suggests that other factors or genetic loci influence INH metabolism, and warrants further investigation in this population.