title: Pharmacokinetics and tolerance of flunitrazepam in neonates and in infants.
abstract: OBJECTIVE
  To study the pharmacokinetics of flunitrazepam (used for sedation in neonates and infants), to determine the influence of both gestational and postnatal age on the pharmacokinetic parameters, and to analyze the relationship between the hemodynamic parameters and flunitrazepam plasma concentration.
  
  
  METHODS
  Flunitrazepam was infused for 20 minutes as a single dose (0.2 mg x kg(-1)) and as multiple doses (0.1 mg x kg(-1)). Six to eight 1-mL blood samples were collected per patient. Flunitrazepam plasma concentration was measured by gas chromatography-mass spectrometry.
  
  
  RESULTS
  Thirty-one patients (25 neonates and six infants) were included in the study. Only three of them received multiple doses. After the single dose (n = 28), half-life was 22.6 +/- 7.3 hours, clearance was 0.15 +/- 0.14 L x kg x h(-1), and volume of distribution was 4.6 +/- 4.1 L x kg(-1) (mean +/- SD). Plasma clearance and volume of distribution significantly increased with postnatal age (P < .05), but no pharmacokinetic parameter varied significantly with gestational age. Diastolic blood pressure significantly decreased with increasing flunitrazepam plasma concentrations (P < .05).
  
  
  CONCLUSIONS
  Postnatal age but not gestational age influenced flunitrazepam pharmacokinetic parameters in neonates and infants. Diastolic blood pressure was inversely correlated to flunitrazepam plasma concentration.
authors.affiliation: Service de Pharmacologie Périnatale et Pédiatrique, Hôpital Saint-Vincent de Paul-Université René Descartes Paris, France.
authors.forename: A
authors.initials: A
authors.lastname: Pariente-Khayat
authors.forename: J M
authors.initials: JM
authors.lastname: Tréluyer
authors.forename: E
authors.initials: E
authors.lastname: Rey
authors.forename: M
authors.initials: M
authors.lastname: Mokhtari
authors.forename: E
authors.initials: E
authors.lastname: Werner
authors.forename: P
authors.initials: P
authors.lastname: Jouvet
authors.forename: P
authors.initials: P
authors.lastname: d'Athis
authors.forename: C
authors.initials: C
authors.lastname: Wood
authors.forename: P
authors.initials: P
authors.lastname: Hubert
authors.forename: F
authors.initials: F
authors.lastname: Hotellier
authors.forename: G
authors.initials: G
authors.lastname: Olive
authors.forename: G
authors.initials: G
authors.lastname: Pons
mesh_terms: D000367:Age Factors; D014151:Anti-Anxiety Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects*; D005260:Female; D005445:Flunitrazepam / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D008401:Gas Chromatography-Mass Spectrometry; D005865:Gestational Age; D006207:Half-Life; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D012121:Respiration, Artificial
chemical_list: D014151:Anti-Anxiety Agents; D005445:Flunitrazepam