title: N-acetyltransferase genotypes and the pharmacokinetics and tolerability of para-aminosalicylic acid in patients with drug-resistant pulmonary tuberculosis.
abstract: 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.
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida, USA sherwin.kenneth.sy@gmail.com.
authors.forename: Sherwin K B
authors.initials: SK
authors.lastname: Sy
authors.affiliation: Division of Clinical Pharmacology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
authors.forename: Lizanne
authors.initials: L
authors.lastname: de Kock
authors.affiliation: Task Applied Science, Bellville, Cape Town, South Africa Division of Physiology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
authors.forename: Andreas H
authors.initials: AH
authors.lastname: Diacon
authors.affiliation: 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.
authors.forename: Cedric J
authors.initials: CJ
authors.lastname: Werely
authors.affiliation: Departments of Ophthalmology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Huiming
authors.initials: H
authors.lastname: Xia
authors.affiliation: Division of Clinical Pharmacology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
authors.forename: Bernd
authors.initials: B
authors.lastname: Rosenkranz
authors.affiliation: 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.
authors.forename: Lize
authors.initials: L
authors.lastname: van der Merwe
authors.affiliation: Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Donald
mesh_terms: D000123:Acetyltransferases / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000483:Alleles; D010131:Aminosalicylic Acid / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000995:Antitubercular Agents / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001191:Arylamine N-Acetyltransferase / Q000235:genetics; D058491:Bacterial Load; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations; D024881:Drug Resistance, Bacterial; D005260:Female; D005838:Genotype; D006801:Humans; D007527:Isoenzymes / Q000235:genetics; D008297:Male; D008826:Microbial Sensitivity Tests; D016012:Poisson Distribution; D012727:Sex Characteristics; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy* / Q000382:microbiology; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents; D003692:Delayed-Action Preparations; D007527:Isoenzymes; D010131:Aminosalicylic Acid; D000123:Acetyltransferases; D001191:Arylamine N-Acetyltransferase; C089384:N-acetyltransferase 1; C478900:NAT2 protein, human