Pharmacokinetics and toxicity of docetaxel: role of CYP3A, MDR1, and GST polymorphisms

Clin Pharmacol Ther. 2006 Jun;79(6):570-80. doi: 10.1016/j.clpt.2006.02.003. Epub 2006 May 2.


Objective: Patients initiating docetaxel chemotherapy were genotyped for CYP3A4, CYP3A5, MDR1, GSTM1, GSTT1, GSTM3, and GSTP1 to identify variability factors of docetaxel pharmacokinetics and toxicity.

Methods: Genotyping was performed by direct sequencing (CYP3A4), real-time polymerase chain reaction (CYP3A5), and polymerase chain reaction-restriction fragment length polymorphism (MDR1 and GST). The clearance and area under the curve of docetaxel were calculated by use of a Bayesian approach. Absolute neutrophil count was recorded twice weekly.

Results: With regard to the pharmacokinetic analysis, 58 patients were included. CYP3A4*1B carriers (*1A/*1B, n=4), who are also CYP3A5*1/*3 carriers, had a significantly higher clearance and lower dose-normalized area under the curve of docetaxel than those with the wild genotype (*1A/*1A, n=53): 55.2+/-13.5 L/h versus 37.3+/-11.7 L/h (P=.01) and 31.4+/-6.2 (microg . h/L)/(mg/m(2)) versus 52.7+/-18.2 (microg . h/L)/(mg/m(2)) (P=.005), respectively. No influence of MDR1 was evidenced. With regard to the pharmacodynamic analysis, febrile neutropenia occurred more frequently in GSTP1*A/*B carriers (31.6% versus 3.7% in *A/*A carriers and 0% in *A/*C, *B/*B, and *B/*C carriers) (P=.037). Grade 3 neutropenia occurred more frequently in 3435TT MDR1 genotype carriers: TT, 100%; CT, 77.3%; and CC, 54.5% (P=.046). No influence of GSTM1, GSTT1, or GSTM3 polymorphisms was evidenced on docetaxel toxicity.

Conclusions: Patients carrying the CYP3A*1B allele may have enhanced docetaxel clearance and may be underexposed, whereas those carrying GSTP1*A/*B and 3435TT genotypes may have excessive hematologic toxicity. Further studies are warranted to determine the usefulness of genotyping before docetaxel treatment.

Publication types

  • Clinical Trial

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • Aged
  • Antineoplastic Agents, Phytogenic / administration & dosage
  • Antineoplastic Agents, Phytogenic / blood
  • Antineoplastic Agents, Phytogenic / pharmacokinetics*
  • Antineoplastic Agents, Phytogenic / toxicity*
  • Area Under Curve
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / genetics
  • DNA / analysis
  • DNA Primers
  • Docetaxel
  • Female
  • Humans
  • Infusions, Intravenous
  • Male
  • Middle Aged
  • Organic Anion Transporters / genetics
  • Polymerase Chain Reaction
  • Polymorphism, Genetic
  • Taxoids / administration & dosage
  • Taxoids / blood
  • Taxoids / pharmacokinetics*
  • Taxoids / toxicity*


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antineoplastic Agents, Phytogenic
  • DNA Primers
  • Organic Anion Transporters
  • Taxoids
  • gonad-specific transporter, human
  • Docetaxel
  • DNA
  • Cytochrome P-450 Enzyme System
  • CYP3A protein, human
  • CYP3A5 protein, human
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human