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Please use this identifier to cite or link to this item: http://hdl.handle.net/123456789/13518

Title: Effect of Genetic Variation of NAT2 on Isoniazid and SLCO1B1 and CES2 on Rifampin Pharmacokinetics in Ghanaian Children with Tuberculosis
Authors: Dompreh, Albert
Tang, Xiaoli
Zhou, Jianlin
Yang, Hongmei
Topletz, Ariel
Ahwireng, Eugene Adu
Antwi, Sampson
Enimil, Antony
Langaee, Taimour
Peloquin, Charles A.
Court, Michael H.
Kwara, Awewura
Keywords: NAT2 acetylator genotypes
SLCO1B1 gene
CES2 gene
single nucleotide
polymorphisms
rifampin pharmacokinetics
isoniazid pharmacokinetics
Issue Date: 2017
Publisher: Antimicrobial Agents and Chemotherapy
Abstract: Isoniazid and rifampin are essential components of first-line antituberculosis (anti-TB) therapy. Understanding the relationship between genetic factors and the pharmacokinetics of these drugs could be useful in optimizing treatment outcomes, but this is understudied in children. We investigated the relationship between N-acetyltransferase type 2 (NAT2) genotypes and isoniazid pharmacokinetics, as well as that between the solute carrier organic anion transporter family member 1B1 (encoded by SLCO1B1) and carboxylesterase 2 (CES2) single nucleotide polymorphisms (SNPs) and rifampin pharmacokinetics in Ghanaian children. Blood samples were collected at times 0, 1, 2, 4, and 8 h postdose in children with tuberculosis on standard first-line therapy for at least 4 weeks. Isoniazid and rifampin concentrations were determined by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, and pharmacokinetic parameters were calculated using noncompartmental analysis. Genotyping of NAT2, SLCO1B1, and CES2 SNPs were performed using validated TaqMan genotyping assays. The Kruskal-Wallis test was used to compare pharmacokinetic parameters among the three genotypic groups and was followed by the Wilcoxon rank sum test for pairwise group comparisons. Genotype status inferred by the NAT2 4-SNP and 7-SNP genotyping panels identified children with a slow acetylator phenotype but not the rapid genotype. For rifampin, only the rare SLCO1B1*1b homozygous variant was associated with rifampin pharmacokinetics. Our findings suggest that NAT2 and SCLCO1B1*1b genotyping may have minimal clinical utility in dosing decisions at the population level in Ghanaian children, but it could be useful at the individual level or in populations that have a high frequency of implicated genotypes. Further studies in other populations are warranted.
Description: This article is published in Antimicrobial Agents and Chemotherapy
URI: http://hdl.handle.net/123456789/13518
Appears in Collections:College of Agric and Natural Resources

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