title: Phenotyping CYP3A using midazolam in cancer and noncancer Asian patients.
abstract: OBJECTIVE
  To investigate CYP3A activity in cancer and noncancer Asian patients using midazolam and to reveal possible alternative traits for phenotyping CYP3A.
  
  
  METHODS
  Intravenous midazolam 2.5 mg or 2.5-8 mg was administered to 27 cancer and 24 noncancer patients, respectively. Plasma was sampled at 0, 0.25, 0.5, 1, 1.5, 2, 3.5 and 5 h after intravenous ultrashort, 30 s infusion. Plasma midazolam and 1'-hydroxymidazolam concentrations were determined using GCMS. The disposition of midazolam and 1'-hydroxymidazolam in these patients was compared. Midazolam clearance was correlated with dose-normalized plasma midazolam concentrations (concentration/per dose).
  
  
  RESULTS
  Clearance (CL) and steady state volume of distribution (Vss) of midazolam (mean +/- SD, 95% confidence level) in cancer (424 +/- 155, 61.3 ml min(-1); 1.21 +/- 0.46, 0.18 l kg(-1)) and noncancer (407 +/- 135, 57.1 ml min(-1); 1.15 +/- 0.33, 0.155 l kg(-1)) patients, respectively, were not different and comparable with published data. Clearance variability was 4-5 fold in both groups. Midazolam clearance correlated significantly with all plasma concentration/per dose at and after the 1-h time point, with a minimum correlation coefficient of r = 0.752, P < 0.001.
  
  
  CONCLUSIONS
  CYP3A activities determined with different doses of midazolam in cancer and noncancer Asian patients showed variability of 4-5-fold and were not different between groups. One to two-fold plasma midazolam concentrations per dose may be feasible as a simple alternative phenotypic trait for hepatic CYP3A activity determination.
authors.affiliation: Department of Pharmacology, National University of Singapore, Singapore. phcleehs@nus.edu.sg
authors.forename: How Sung
authors.initials: HS
authors.lastname: Lee
authors.forename: Boon Cher
authors.initials: BC
authors.lastname: Goh
authors.forename: Lu
authors.initials: L
authors.lastname: Fan
authors.forename: Yok Moi
authors.initials: YM
authors.lastname: Khoo
authors.forename: Lingzhi
authors.initials: L
authors.lastname: Wang
authors.forename: Robert
authors.initials: R
authors.lastname: Lim
authors.forename: Ai Bee
authors.initials: AB
authors.lastname: Ong
authors.forename: Charlotte
authors.initials: C
authors.lastname: Chua
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D001208:Asia / Q000208:ethnology; D002851:Chromatography, High Pressure Liquid; D051544:Cytochrome P-450 CYP3A; D005260:Female; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D008875:Middle Aged; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*; D010641:Phenotype
chemical_list: C040081:1-hydroxymethylmidazolam; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D008874:Midazolam