Pharmacogenetic pathway analysis of docetaxel elimination.
The purpose of this study was to evaluate the affinity of docetaxel for 14 transporter proteins and assess the functional significance of 17 variants in five genes involved in drug elimination. Among the transfected models investigated, OATP1B3 (SLCO1B3) was identified as the most efficient influx transporter for docetaxel. None of the observed genotypes (SLCO1B3, ABCB1, and ABCC2) was related with docetaxel clearance in 92 white patients (P > 0.17). However, the simultaneous presence of the CYP3A4*1B and CYP3A5*1A alleles was associated with a 64% increase in docetaxel clearance (P = 0.0015), independent of both sex and CYP3A activity (as determined using the erythromycin breath test). This haplotype was also associated with increased midazolam clearance in another population (P = 0.0198). An analysis of the CYP3A locus among CEPH-HapMap samples revealed that CYP3A4*1B is present exclusively among a subset of CYP3A5 expressors. Therefore, future studies should first stratify the population on the basis of CYP3A5 genotype and then compare CYP3A activity between individuals with and without the CYP3A4*1B allele.
Baker
S D
SD
Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee, USA. sharyn.baker@stjude.org
Verweij
J
J
Cusatis
G A
GA
van Schaik
R H
RH
Marsh
S
S
Orwick
S J
SJ
Franke
R M
RM
Hu
S
S
Schuetz
E G
EG
Lamba
V
V
Messersmith
W A
WA
Wolff
A C
AC
Carducci
M A
MA
Sparreboom
A
A
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002460:Cell Line; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D000077143:Docetaxel; D004285:Dogs; D005260:Female; D005787:Gene Frequency / Q000187:drug effects / Q000502:physiology; D014644:Genetic Variation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000502:physiology; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D010597:Pharmacogenetics / Q000379:methods*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D043823:Taxoids / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology*; D014982:Xenopus laevis; D055815:Young Adult
C000715087:ABCC2 protein, human; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D043823:Taxoids; D000077143:Docetaxel; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A