Pharmacokinetics and toxicity of docetaxel: role of CYP3A, MDR1, and GST polymorphisms.
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.
Tran
A
A
Ecole Pratique des Hautes Etudes, Pharmacologie, Faculté de Médecine, Groupe Hospitalier Cochin St Vincent de Paul, AP-HP, Université Paris-Descartes, Paris, France.
Jullien
V
V
Alexandre
J
J
Rey
E
E
Rabillon
F
F
Girre
V
V
Dieras
V
V
Pons
G
G
Goldwasser
F
F
Tréluyer
J M
JM
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D004247:DNA / Q000032:analysis; D017931:DNA Primers; D000077143:Docetaxel; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000235:genetics; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D043823:Taxoids / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System; D004247:DNA; D017931:DNA Primers; D000077143:Docetaxel; D027361:Organic Anion Transporters; D043823:Taxoids; C487009:SLCO6A1 protein, human; C104464:CYP3A protein, human; C510164:CYP3A5 protein, human; C510163:CYP3A4 protein, human