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N-acetyltransferase 2 genotypes amongst Zulu Speaking South Africans and isoniazid/N-acetyl-isoniazid pharmacokinetics during anti-tuberculosis treatment.
Antimicrob Agents Chemother. 2020 Jan 21 [Online ahead of print]AA

Abstract

BACKGROUND

Distribution of N-acetyltransferase2 (NAT2) polymorphisms varies considerably among different ethnic groups. Information on NAT2 single-nucleotide polymorphisms in South African population is limited. 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 determination of 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%) had intermediate (NAT2*5/12), and 12/120 (11.7%) had rapid genotype (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 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.

Authors+Show Affiliations

South African Medical Research Council, Durban, South Africa thuli.mthiyane@mrc.ac.za.Wellcome Trust Liverpool Glasgow Centre for Global Health Research, Liverpool, UK. Institute of Infection and Global Health, University of Liverpool, Liverpool, UK. Africa Health Research Institute, Durban, South Africa.Africa Health Research Institute, Durban, South Africa.South African Medical Research Council, Biostatistics Department, Durban, South Africa.South African Medical Research Council, Biostatistics Department, Durban, South Africa.Department of Molecular and Clinical Pharmacology, University of Liverpool, United Kingdom.South African Medical Research Council, Durban, South Africa.Lung Infection and Immunity Unit, Division of Pulmonology, Department of Medicine, University of Cape Town, Cape Town, South Africa.Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.South African Medical Research Council, Durban, South Africa. Africa Health Research Institute, Durban, South Africa.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31964788

Citation

Mthiyane, Thuli, et al. "N-acetyltransferase 2 Genotypes Amongst Zulu Speaking South Africans and isoniazid/N-acetyl-isoniazid Pharmacokinetics During Anti-tuberculosis Treatment." Antimicrobial Agents and Chemotherapy, 2020.
Mthiyane T, Millard J, Adamson J, et al. N-acetyltransferase 2 genotypes amongst Zulu Speaking South Africans and isoniazid/N-acetyl-isoniazid pharmacokinetics during anti-tuberculosis treatment. Antimicrob Agents Chemother. 2020.
Mthiyane, T., Millard, J., Adamson, J., Balakrishna, Y., Connolly, C., Owen, A., Rustomjee, R., Dheda, K., McIlleron, H., & Pym, A. S. (2020). N-acetyltransferase 2 genotypes amongst Zulu Speaking South Africans and isoniazid/N-acetyl-isoniazid pharmacokinetics during anti-tuberculosis treatment. Antimicrobial Agents and Chemotherapy. https://doi.org/10.1128/AAC.02376-19
Mthiyane T, et al. N-acetyltransferase 2 Genotypes Amongst Zulu Speaking South Africans and isoniazid/N-acetyl-isoniazid Pharmacokinetics During Anti-tuberculosis Treatment. Antimicrob Agents Chemother. 2020 Jan 21; PubMed PMID: 31964788.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - N-acetyltransferase 2 genotypes amongst Zulu Speaking South Africans and isoniazid/N-acetyl-isoniazid pharmacokinetics during anti-tuberculosis treatment. AU - Mthiyane,Thuli, AU - Millard,James, AU - Adamson,John, AU - Balakrishna,Yusentha, AU - Connolly,Cathy, AU - Owen,Andrew, AU - Rustomjee,Roxana, AU - Dheda,Keertan, AU - McIlleron,Helen, AU - Pym,Alexander S, Y1 - 2020/01/21/ PY - 2020/1/23/entrez JF - Antimicrobial agents and chemotherapy JO - Antimicrob. Agents Chemother. N2 - BACKGROUND: Distribution of N-acetyltransferase2 (NAT2) polymorphisms varies considerably among different ethnic groups. Information on NAT2 single-nucleotide polymorphisms in South African population is limited. 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 determination of 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%) had intermediate (NAT2*5/12), and 12/120 (11.7%) had rapid genotype (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 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. SN - 1098-6596 UR - https://www.unboundmedicine.com/medline/citation/31964788/N-acetyltransferase_2_genotypes_amongst_Zulu_Speaking_South_Africans_and_isoniazid/N-acetyl-isoniazid_pharmacokinetics_during_anti-tuberculosis_treatment L2 - http://aac.asm.org/cgi/pmidlookup?view=long&pmid=31964788 DB - PRIME DP - Unbound Medicine ER -
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