N-acetyltransferase genotypes and the pharmacokinetics and tolerability of para-aminosalicylic acid in patients with drug-resistant pulmonary tuberculosis.
| Autor: | Sy SK; Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida, USA sherwin.kenneth.sy@gmail.com., de Kock L; Division of Clinical Pharmacology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa., Diacon AH; Task Applied Science, Bellville, Cape Town, South Africa Division of Physiology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa., Werely CJ; MRC Centre for Tuberculosis Research, DST-NRF Centre of Excellence for Biomedical TB Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa., Xia H; Departments of Ophthalmology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Rosenkranz B; Division of Clinical Pharmacology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa., van der Merwe L; MRC Centre for Tuberculosis Research, DST-NRF Centre of Excellence for Biomedical TB Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa Department of Statistics, Faculty of Natural Sciences, University of the Western Cape, Cape Town, South Africa., Donald PR; Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa. |
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| Jazyk: | angličtina |
| Zdroj: | Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2015 Jul; Vol. 59 (7), pp. 4129-38. Date of Electronic Publication: 2015 May 11. |
| DOI: | 10.1128/AAC.04049-14 |
| Abstrakt: | The aim of this study was to examine the relationships between N-acetyltransferase genotypes, pharmacokinetics, and tolerability of granular slow-release para-aminosalicylic acid (GSR-PAS) in tuberculosis patients. The study was a randomized, two-period, open-label, crossover design wherein each patient received 4 g GSR-PAS twice daily or 8 g once daily alternately. The PAS concentration-time profiles were modeled by a one-compartment disposition model with three transit compartments in series to describe its absorption. Patients' NAT1 and NAT2 genotypes were determined by sequencing and restriction enzyme analysis, respectively. The number of daily vomits was modeled by a Poisson probability mass function. Comparisons of other tolerability measures by regimens, gender, and genotypes were evaluated by a linear mixed-effects model. The covariate effects associated with efavirenz, gender, and NAT1*3, NAT1*14, and NAT2*5 alleles corresponded to 25, 37, -17, -48, and -27% changes, respectively, in oral clearance of PAS. The NAT1*10 allele did not influence drug clearance. The time above the MIC of 1 mg/liter was significantly different between the two regimens but not influenced by the NAT1 or NAT2 genotypes. The occurrence and intensity of intolerance differed little between regimens. Four grams of GSR-PAS twice daily but not 8 g once daily ensured concentrations exceeding the MIC (1 mg/liter) throughout the dosing interval; PAS intolerance was not related to maximum PAS concentrations over the doses studied and was not more frequent after once-daily dosing. We confirm that the slow phenotype conferred by the NAT1*14 and NAT1*3 alleles resulted in higher PAS exposure but found no evidence of increased activity of the NAT1*10 allele. (Copyright © 2015, American Society for Microbiology. All Rights Reserved.) |
| Databáze: | MEDLINE |
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