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

Rui Zhu, Jennifer J. Kiser, Heiner I. Seifart, Cedric J. Werely, Charles D Mitchell, David Z. D'Argenio, Courtney V. Fletcher

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)511-519
Number of pages9
JournalJournal of Clinical Pharmacology
Volume52
Issue number4
DOIs
StatePublished - Apr 1 2012

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Pharmacogenetics
Isoniazid
HIV
Genotype
Enzymes
Body Weight
Latent Tuberculosis
Acetylation
Pharmacokinetics
Population

Keywords

  • enzyme maturation
  • genetic polymorphism
  • Infants
  • pharmacogenetics
  • population pharmacokinetics

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology

Cite this

The pharmacogenetics of NAT2 enzyme maturation in perinatally HIV exposed infants receiving isoniazid. / Zhu, Rui; Kiser, Jennifer J.; Seifart, Heiner I.; Werely, Cedric J.; Mitchell, Charles D; D'Argenio, David Z.; Fletcher, Courtney V.

In: Journal of Clinical Pharmacology, Vol. 52, No. 4, 01.04.2012, p. 511-519.

Research output: Contribution to journalArticle

Zhu, Rui ; Kiser, Jennifer J. ; Seifart, Heiner I. ; Werely, Cedric J. ; Mitchell, Charles D ; D'Argenio, David Z. ; Fletcher, Courtney V. / The pharmacogenetics of NAT2 enzyme maturation in perinatally HIV exposed infants receiving isoniazid. In: Journal of Clinical Pharmacology. 2012 ; Vol. 52, No. 4. pp. 511-519.
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