title: 4β-hydroxycholesterol as an endogenous CYP3A marker in cancer patients treated with taxanes.
abstract: OBJECTIVE
  Taxanes are anti-cancer agents used to treat several types of solid tumours. They are metabolized by cytochrome P450 (CYP) 3A, displaying a large pharmacokinetic (PK) variability. In this study, we evaluated the endogenous CYP3A4 marker 4β-hydroxycholesterol (4β-OHC) as a potential individual taxane PK predictor.
  
  
  METHODS
  Serum 4β-OHC and cholesterol concentrations were determined in 291 paclitaxel and 151 docetaxel-treated patients, and were subsequently correlated with taxane clearance.
  
  
  RESULTS
  In the patients treated with paclitaxel, no clinically relevant correlations between the 4β-OHC or 4β-OHC : cholesterol ratio and paclitaxel clearance were found. In the patients treated with docetaxel, 4β-OHC concentration was weakly correlated with docetaxel clearance in males (r = 0.35 P = 0.01, 95% CI 0.08, 0.58). Of the 10% patients with taxane outlier clearance values, 4β-OHC did correlate with docetaxel clearance in males (r = 0.76, P = 0.03, 95% CI 0.12, 0.95).
  
  
  CONCLUSIONS
  There was no clinical correlation between paclitaxel clearance and the CYP3A4 activity markers 4β-OHC or the 4β-OHC : cholesterol ratio. A weak correlation was observed between 4β-OHC and docetaxel clearance, but only in males. This endogenous CYP3A4 marker has limited predictive value for taxane clearance in patients.
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, 's-Gravendijkwal 230, 3015CE, Rotterdam.
authors.forename: Anne-Joy M
authors.initials: AJ
authors.lastname: de Graan
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, 's-Gravendijkwal 230, 3015CE, Rotterdam.|Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, 262 Danny Thomas Place, 38105-3678, Memphis, TN, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Sparreboom
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, 's-Gravendijkwal 230, 3015CE, Rotterdam.
authors.forename: Peter
authors.initials: P
authors.lastname: de Bruijn
authors.affiliation: Department of Clinical Chemistry, Erasmus University Medical Center, 's-Gravendijkwal 230, 3015CE, Rotterdam, the Netherlands.
authors.forename: Evert
authors.initials: E
authors.lastname: de Jonge
authors.affiliation: Department of Trials and Statistics, Erasmus University Medical Center, 's-Gravendijkwal 230, 3015CE, Rotterdam, the Netherlands.
authors.forename: Bronno
authors.initials: B
authors.lastname: van der Holt
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, 's-Gravendijkwal 230, 3015CE, Rotterdam.
authors.forename: Erik A C
authors.initials: EA
authors.lastname: Wiemer
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, 's-Gravendijkwal 230, 3015CE, Rotterdam.
authors.forename: Jaap
authors.initials: J
authors.lastname: Verweij
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, 's-Gravendijkwal 230, 3015CE, Rotterdam.
authors.forename: Ron H J
authors.initials: RH
authors.lastname: Mathijssen
authors.affiliation: Department of Clinical Chemistry, Erasmus University Medical Center, 's-Gravendijkwal 230, 3015CE, Rotterdam, the Netherlands.
authors.forename: Ron H N
authors.initials: RH
authors.lastname: van Schaik
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D000077143:Docetaxel; D005260:Female; D006801:Humans; D006888:Hydroxycholesterols / Q000097:blood*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology; D017239:Paclitaxel / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D043823:Taxoids / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D006888:Hydroxycholesterols; D043823:Taxoids; D000077143:Docetaxel; C099828:cholest-5-ene-3,4-diol; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D017239:Paclitaxel
keywords: 4β-hydroxycholesterol; CYP3A activity; endogenous marker; pharmacokinetics; taxanes