title: High Plasma Concentrations of Zidovudine (AZT) Do Not Parallel Intracellular Concentrations of AZT-Triphosphates in Infants During Prevention of Mother-to-Child HIV-1 Transmission.
abstract: Zidovudine (AZT) is mainly used to prevent mother-to-child HIV-1 transmission (PMTCT). Despite serious concerns on AZT-associated toxicity, there is little information on pharmacokinetics of intracellular AZT metabolites in infants.
  
  
  
  We conducted a prospective study in 31 HIV-uninfected infants who received AZT for PMTCT. Blood samples were obtained from 14 infants on postdelivery days (PDD) 1, 7, 14, and 28 and from 17 infants at 0 and 4 hours after dosing on PDD-1. Plasma AZT concentrations (pAZT) and intracellular concentrations of AZT-monophosphate (icAZT-MP), diphosphate (icAZT-DP), and triphosphate (icAZT-TP) were determined.
  
  
  
  Plasma AZT and icAZT-MP concentrations were 2713 nmol/L and 79 fmol/10 cells in PDD-1, but decreased to 1437 nmol/L and 31 fmol/10 cells by PDD-28 (P = 0.02 and P = 0.07 for all PDDs, respectively), whereas those of icAZT-DP and icAZT-TP remained low throughout the sampling period (P = 0.29 and P = 0.61 for all PDDs, respectively) There were no differences in icAZT-TP between infants of the 2 mg/kg 4 times a day dose and 4 mg/kg twice daily dose (P = 0.25), whereas pAZT and icAZT-MP levels were higher in the latter (P < 0.01 and <0.01, respectively). The pAZT and icAZT-MP significantly increased from 0 to 4 hours after dosing (P < 0.001 and <0.001, respectively), whereas icAZT-DP, icAZT-TP levels were not changed (P = 0.41 and 0.33, respectively).
  
  
  
  The level of icAZT-TP did not change with age, time, or a single dose despite the wide range of pAZT concentration. A safer dosage needs to be determined because high pAZT levels do not parallel those of icAZT-TP.
authors: *AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan; †Department of Microbiology and Immunology, School of Medicine, Keio University, Tokyo, Japan; Departments of ‡Pediatrics; §Obstetrics and Gynecology, National Center for Global Health and Medicine, Tokyo, Japan; ‖Department of Infectious Disease, National Hospital of Pediatrics, Hanoi, Vietnam; ¶Department of Scientific Research, National Hospital of Obstetrics and Gynecology, Hanoi, Vietnam; and #National Hospital of Tropical Diseases, Hanoi, Vietnam.
authors: Ei
authors: E
authors: Kinai
authors: Shingo
authors: S
authors: Kato
authors: Shinichi
authors: S
authors: Hosokawa
authors: Miyuki
authors: M
authors: Sadatsuki
authors: Hiroyuki
authors: H
authors: Gatanaga
authors: Yoshimi
authors: Y
authors: Kikuchi
authors: Nguyen Van
authors: NV
authors: Lam
authors: Do Quan
authors: do Q
authors: Ha
authors: Nguyen Van
authors: NV
authors: Kinh
authors: Nguyen Thanh
authors: NT
authors: Liem
authors: Shinichi
authors: S
authors: Oka
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000097:blood / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D054306:Dideoxynucleotides / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000517:prevention & control* / Q000635:transmission*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007231:Infant, Newborn; D018445:Infectious Disease Transmission, Vertical / Q000517:prevention & control*; D008137:Longitudinal Studies; D008297:Male; D009035:Mothers; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000188:drug therapy* / Q000276:immunology; D011446:Prospective Studies; D013942:Thymine Nucleotides / Q000097:blood / Q000493:pharmacokinetics*; D016896:Treatment Outcome; D055815:Young Adult; D015215:Zidovudine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D019380:Anti-HIV Agents; D054306:Dideoxynucleotides; D013942:Thymine Nucleotides; D015215:Zidovudine; C052873:zidovudine triphosphate