The pharmacogenetics of NAT2 enzyme maturation in perinatally HIV exposed infants receiving isoniazid

J Clin Pharmacol. 2012 Apr;52(4):511-9. doi: 10.1177/0091270011402826. Epub 2011 May 10.


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.

Publication types

  • Clinical Trial, Phase II
  • Clinical Trial, Phase III
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Administration, Oral
  • Age Factors
  • Antitubercular Agents / administration & dosage
  • Antitubercular Agents / pharmacokinetics*
  • Antitubercular Agents / therapeutic use
  • Arylamine N-Acetyltransferase / genetics*
  • Child, Preschool
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Female
  • Genotype
  • HIV Infections / transmission
  • Humans
  • Infant
  • Infectious Disease Transmission, Vertical
  • Isoniazid / administration & dosage
  • Isoniazid / pharmacokinetics*
  • Isoniazid / therapeutic use*
  • Latent Tuberculosis / prevention & control
  • Male
  • Pharmacogenetics
  • Pregnancy
  • Pregnancy Complications, Infectious / epidemiology
  • Prospective Studies
  • South Africa
  • Tuberculosis / prevention & control


  • Antitubercular Agents
  • Arylamine N-Acetyltransferase
  • NAT2 protein, human
  • Isoniazid