N-Acetyltransferase Genotypes and the Pharmacokinetics and Tolerability ofpara-Aminosalicylic Acid in Patients with Drug-Resistant Pulmonary Tuberculosis

Abstract

ABSTRACTThe aim of this study was to examine the relationships betweenN-acetyltransferase genotypes, pharmacokinetics, and tolerability of granular slow-releasepara-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'NAT1andNAT2genotypes 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, andNAT1*3,NAT1*14, andNAT2*5alleles corresponded to 25, 37, −17, −48, and −27% changes, respectively, in oral clearance of PAS. TheNAT1*10allele 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 theNAT1orNAT2genotypes. 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 theNAT1*14andNAT1*3alleles resulted in higher PAS exposure but found no evidence of increased activity of theNAT1*10allele.