title: Dexamethasone as a probe for docetaxel clearance.
abstract: OBJECTIVE
  A pilot study was conducted in 23 patients in order to assess the correlation between docetaxel clearance (CL) and pharmacokinetics of dexamethasone. Dexamethasone is mainly 6-beta hydroxylated by CYP3A4, and is regularly used as standard docetaxel premedication. Genotyping of known functional single nucleotide polymorphism (SNP) of CYP3A5 (G22893A) and mdr-1 (G2677T, G2677A, and C3435T) have been performed in order to tentatively correlate genotype with docetaxel and dexamethasone pharmacokinetics.
  
  
  METHODS
  To be eligible for this study, patients were required to have a solid malignancy for which docetaxel was indicated. A population pharmacokinetic approach was used to determine individual pharmacokinetic parameters of both docetaxel and dexamethasone by Bayesian analysis, and to screen relationships between docetaxel CL and patients' demographic, phenotype and genotype covariates.
  
  
  RESULTS
  Three different pharmacokinetic parameters of dexamethasone were significantly correlated with docetaxel CL: dexamethasone plasma clearance (DPC) that ranged between 7.7 and 27.2 l/h, urinary amount of 6beta-hydroxydexamethasone, and the ratio between urinary amount of 6beta-hydroxydexamethasone and unchanged dexamethasone. The best covariate model was docetaxel CL (l/h) = 356 x fu(alpha1-AG) x (1-0.17 x HPMT)(1+0.126 x DPC) where fu(alpha1-AG) is the unbound plasma fraction of docetaxel calculated from alpha1-acid glycoprotein plasma level, and HPMT is hepatic metastasis coded as 1 if present or 0 if absent. No significant difference in docetaxel CL was observed between the several genotypes.
  
  
  CONCLUSIONS
  Dexamethasone may be used as a probe to predict docetaxel clearances, hence reducing interindividual variability.
authors.affiliation: Institut Claudius-Regaud, Université Paul-Sabatier, 31052 Toulouse, France.
authors.forename: Florent
authors.initials: F
authors.lastname: Puisset
authors.forename: Etienne
authors.initials: E
authors.lastname: Chatelut
authors.forename: Florence
authors.initials: F
authors.lastname: Dalenc
authors.forename: Florent
authors.initials: F
authors.lastname: Busi
authors.forename: Thierry
authors.initials: T
authors.lastname: Cresteil
authors.forename: Joëlle
authors.initials: J
authors.lastname: Azéma
authors.forename: Muriel
authors.initials: M
authors.lastname: Poublanc
authors.forename: Isabelle
authors.initials: I
authors.lastname: Hennebelle
authors.forename: Thierry
authors.initials: T
authors.lastname: Lafont
authors.forename: Christine
authors.initials: C
authors.lastname: Chevreau
authors.forename: Henri
authors.initials: H
authors.lastname: Roché
mesh_terms: D000328:Adult; D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000493:pharmacokinetics*; D015415:Biomarkers; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000494:pharmacology; D003907:Dexamethasone / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000077143:Docetaxel; D005260:Female; D019450:Genes, MDR; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D015203:Reproducibility of Results; D043823:Taxoids / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D015415:Biomarkers; D043823:Taxoids; D000077143:Docetaxel; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human