title: The pharmacogenetics of NAT2 enzyme maturation in perinatally HIV exposed infants receiving isoniazid.
abstract: The roles of the NAT2 genotype and enzyme maturation on isoniazid pharmacokinetics were investigated in South African infants with perinatal HIV exposure enrolled in a randomized, double-blind, controlled trial of isoniazid for prevention of tuberculosis disease and latent infection. Plasma concentration-time measurements of isoniazid from 151 infants (starting at 3-4 months of age) receiving isoniazid 10 to 20 mg/kg/d orally during the course of the 24-month study were incorporated in a population analysis along with NAT2 genotype, body weight, age, and sex. The results showed a different NAT2 enzyme maturation profile for each of the 3 acetylation groups, with the 70-kg body weight-normalized typical apparent clearance for the fast and intermediate acetylators increasing from 14.25 L/h and 10.88 L/h at 3 months of age to 22.84 L/h and 15.58 L/h at 24 months of age, respectively, with no significant change in the apparent clearance of the slow group during this period. A hypothesis is proposed to explain the genotype-dependent enzyme maturation processes for the NAT2 enzyme.
authors.affiliation: Biomedical Simulations Resource (BMSR), University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhu
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Kiser
authors.forename: Heiner I
authors.initials: HI
authors.lastname: Seifart
authors.forename: Cedric J
authors.initials: CJ
authors.lastname: Werely
authors.forename: Charles D
authors.initials: CD
authors.lastname: Mitchell
authors.forename: David Z
authors.initials: DZ
authors.lastname: D'Argenio
authors.forename: Courtney V
authors.initials: CV
authors.lastname: Fletcher
mesh_terms: D000284:Administration, Oral; D000367:Age Factors; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000635:transmission; D006801:Humans; D007223:Infant; D018445:Infectious Disease Transmission, Vertical; D007538:Isoniazid / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D055985:Latent Tuberculosis / Q000517:prevention & control; D008297:Male; D010597:Pharmacogenetics; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000453:epidemiology; D011446:Prospective Studies; D013019:South Africa; D014376:Tuberculosis / Q000517:prevention & control
chemical_list: D000995:Antitubercular Agents; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human; D007538:Isoniazid