Full-Gene Sequencing Analysis of
            <i>NAT2</i>
            and its Relationship with Isoniazid Pharmacokinetics in Venezuelan Children with Tuberculosis

Verhagen, Lilly M.; Coenen, Marieke J. H.; López, Diana M.; Garcia, Jenny; Waard, Jacobus H. de; Schijvenaars, Mascha M.V.A.P.; Hermans, Peter W. M.; Aarnoutse, Rob E.

doi:10.2217/pgs.13.230

Cited by 16 publications

(14 citation statements)

References 36 publications

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“…1). Unlike the trimodal distribution of isoniazid pharmacokinetics reported in some studies in adults (11,12), the bimodal distribution observed in our study is consistent with other studies in children, in which the pharmacokinetic parameters in those rapid and intermediate genotypes were similar (13,26,27). The bimodal distribution of NAT2 acetylator phenotype in children may be explained by differences in enzyme maturation with age.…”

Section: Discussionsupporting

confidence: 88%

Effect of Genetic Variation of NAT2 on Isoniazid and SLCO1B1 and CES2 on Rifampin Pharmacokinetics in Ghanaian Children with Tuberculosis

Dompreh

Tang

Zhou

et al. 2018

Antimicrob Agents Chemother

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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 () genotypes and isoniazid pharmacokinetics, as well as that between the solute carrier organic anion transporter family member 1B1 (encoded by ) and carboxylesterase 2 () 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 ,, and 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 4-SNP and 7-SNP genotyping panels identified children with a slow acetylator phenotype but not the rapid genotype. For rifampin, only the rare homozygous variant was associated with rifampin pharmacokinetics. Our findings suggest that and 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.

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Section: Discussionsupporting

confidence: 88%

Effect of Genetic Variation of NAT2 on Isoniazid and SLCO1B1 and CES2 on Rifampin Pharmacokinetics in Ghanaian Children with Tuberculosis

Dompreh

Tang

Zhou

et al. 2018

Antimicrob Agents Chemother

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“…Adverse drug reaction is linked to developmental changes of drug metabolism, so it has age-dependent predisposition [33] , [34] , which might explain the different impacts of the GST polymorphisms on the risk of ATHD between children and adults. Indeed, The ontogeny of both NAT and CYP2E1 has been reported in children [35] – [37] , who had a lower metabolism capacity as compared to adults, thereby, reducing the formation of hepatotoxic metabolites produced by NAT and CYP2E1. As a consequence, the detoxification burden is reduced and the impacts of GST polymorphisms on ATHD might be less important in children as compared to adults.…”

Section: Discussionmentioning

confidence: 99%

Impact of Glutathione S-Transferase M1 and T1 on Anti-Tuberculosis Drug–Induced Hepatotoxicity in Chinese Pediatric Patients

Liu

Jiao

et al. 2014

PLoS ONE

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BackgroundAnti-tuberculosis drug induced hepatotoxicity (ATDH) is a major adverse drug reaction associated for anti-tuberculosis therapy. The glutathione S-transferases (GST) plays a crucial role in the detoxification of hepatotoxic metabolites of anti-tuberculosis drugs.An association between GSTM1/GSTT1 null mutations and increased risk of ATDH has been demonstrated in adults. Given the ethnic differences and developmental changes, our study aims to investigate the potential impacts of GSTM1/GSTT1genotypes on the development of ATDH in Han Chinese children treated with anti-tuberculosis therapy.MethodsChildren receiving anti-tuberculosis therapy with or without evidence of ATDH were considered as the cases or controls, respectively. The GSTM1 and GSTT1 genotyping were performed using the polymerase chain reaction.ResultsOne hundred sixty-three children (20 cases and 143 controls) with a mean age of 4.7 years (range: 2 months-14.1 years) were included. For the GSTM1, 14 (70.0%) cases and 96 (67.1%) controls had homozygous null mutations. For the GSTT1, 13 (65.0%) cases and 97 (67.8%) controls had homozygous null mutations. Neither the GSTM1, nor the GSTT1 polymorphism was significantly correlated with the occurrence of ATHD.ConclusionOurresults did not support the GSTM1 and GSTT1 polymorphisms as the predictors of ADTH in Chinese Han children treated with anti-tuberculosis drugs. An age-related association between pharmacogenetics and ATHD need to be confirmed in the further study.

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“…The impact of mutations in N-acetyl transferase 2(NAT2) genes controlling conversion of isoniazid to acetyl-isoniazid in the intestinal and hepatic cells, is well known. A trimodal distribution of isoniazid exposures is described, although in many studies the respective distributions of the apparent clearance for intermediate and rapid metabolizers are not clearly distinguished [71][72][73]. The AUC among slow acetylators is typically 2-to 3-fold greater than in rapid acetylators.…”

Section: Pharmacogenetic Variationmentioning

confidence: 99%

Current research toward optimizing dosing of first-line antituberculosis treatment

McIlleron

Chirehwa

2018

Expert Review of Anti-infective Therapy

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Introduction: Drug concentrations in tuberculosis patients on standard regimens vary widely with clinically important consequences.Areas covered: We review the available literature identifying factors correlated with pharmacokinetic variability of antituberculosis drugs. Based on population pharmacokinetic models and the weight, height, and sex distributions in a large data base of African tuberculosis patients, we propose simplified weight-based doses of the available fixed dose combination(FDC) for adults with drug susceptible tuberculosis. Emerging studies will support optimized weight-based dosing for children. Other sources of important pharmacokinetic variability include genetic variants, drug-drug interactions, formulation quality, and methods of preparation and administration.Expert commentary: Optimized weight band-based dosing will result in more equitable distribution of drug exposures by weight. The use of high doses of isoniazid in patients with drug-resistant tuberculosis would be safer and more effective if a feasible test was developed to allow stratified dosing according to acetylator type. There is an urgent need for more suitable formulations of many second-line drugs for children. The adoption of new technologies and efficient FDC design may allow further advances for patients and treatment programs. Lastly, current efforts to ensure adequate quality of antituberculosis drug products are not preventing the use of substandard products to treat patients with tuberculosis.

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Full-Gene Sequencing Analysis of NAT2 and its Relationship with Isoniazid Pharmacokinetics in Venezuelan Children with Tuberculosis

Abstract: In Venezuelan children a clear difference in isoniazid pharmacokinetics and acetylator phenotype between genotypically slow and genotypically intermediate or rapid acetylating children was observed. Original submitted 31 July 2013; Revision submitted 11 November 2013.

Cited by 16 publications

References 36 publications

Effect of Genetic Variation of NAT2 on Isoniazid and SLCO1B1 and CES2 on Rifampin Pharmacokinetics in Ghanaian Children with Tuberculosis

Effect of Genetic Variation of NAT2 on Isoniazid and SLCO1B1 and CES2 on Rifampin Pharmacokinetics in Ghanaian Children with Tuberculosis

Impact of Glutathione S-Transferase M1 and T1 on Anti-Tuberculosis Drug–Induced Hepatotoxicity in Chinese Pediatric Patients

Current research toward optimizing dosing of first-line antituberculosis treatment

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