title: Contribution of midazolam and its 1-hydroxy metabolite to preoperative sedation in children: a pharmacokinetic-pharmacodynamic analysis.
abstract: BACKGROUND
  Oral midazolam is widely used for preoperative sedation in children. We have studied the pharmacokinetics (PK) of both midazolam and its active 1-hydroxy metabolite and their contributions to sedative effect in 45 children attending for day surgery.
  
  
  METHODS
  Blood samples (two per individual) were collected at the beginning and end of the surgical procedure. Plasma midazolam and 1-hydroxymidazolam (1-OHMDZ) were measured by HPLC. Sedation score (score: 1 = awake, 2 = drowsy/asleep) was recorded at the same time as the first blood sample. The population-PK software P-Pharm was used to analyse the data. Age, weight, sex, concomitant drugs, and the metabolic ratio, 1-OHMDZ/midazolam were investigated as co-variates of the PK of midazolam and 1-OHMDZ. The pharmacokinetic-pharmacodynamic (PK-PD) modelling of the score in relation to plasma midazolam and 1-OHMDZ was performed using logistic regression analysis.
  
  
  RESULTS
  A median dose of 0.5 mg kg-1 was given to the children, median age 5 yr (range from 9 months to 12 yr) and weight 21 kg (range 8-75 kg). Average concentrations of midazolam 150 ng ml-1 and 1-OHMDZ 90 ng ml-1 were observed in the first plasma samples. These concentrations resulted in an odds ratio of 4 in favour of score 2 vs 1. The best PK-PD model included both midazolam and 1-OHMDZ as active moieties and predicted correct scores in 86% of cases.
  
  
  CONCLUSIONS
  Studies of midazolam should evaluate the contribution of 1-OHMDZ to the overall PD effect. The metabolite 1-OHMDZ has approximately half the activity of the parent drug and can compensate for at least part of the decreased effect due to increased midazolam metabolism.
authors.affiliation: University of Sheffield, Academic Unit of Molecular Pharmacology and Pharmacogenetics, Division of Clinical Sciences (South), Royal Hallamshire Hospital, Sheffield S10 2JF, UK.
authors.forename: T N
authors.initials: TN
authors.lastname: Johnson
authors.forename: A
authors.initials: A
authors.lastname: Rostami-Hodjegan
authors.forename: J M
authors.initials: JM
authors.lastname: Goddard
authors.forename: M S
authors.initials: MS
authors.lastname: Tanner
authors.forename: G T
authors.initials: GT
authors.lastname: Tucker
mesh_terms: D000284:Administration, Oral; D002675:Child, Preschool; D003243:Consciousness / Q000187:drug effects; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives / Q000097:blood / Q000493:pharmacokinetics*; D007223:Infant; D008297:Male; D008874:Midazolam / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics*; D011300:Preoperative Care / Q000379:methods*
chemical_list: D006993:Hypnotics and Sedatives; C040081:1-hydroxymethylmidazolam; D008874:Midazolam