PXR, CAR and HNF4alpha genotypes and their association with pharmacokinetics and pharmacodynamics of docetaxel and doxorubicin in Asian patients.
Previously studied candidate genes have failed to account for inter-individual variability of docetaxel and doxorubicin disposition and effects. We genotyped the transcriptional regulators of CYP3A and ABCB1 in 101 breast cancer patients from 3 Asian ethnic groups, that is, Chinese, Malays and Indians, in correlation with the pharmacokinetics and pharmacodynamics of docetaxel and doxorubicin. While there was no ethnic difference in docetaxel and doxorubicin pharmacokinetics, ethnic difference in docetaxel- (ANOVA, P=0.001) and doxorubicin-induced (ANOVA, P=0.003) leukocyte suppression was observed, with Chinese and Indians experiencing greater degree of docetaxel-induced myelosuppression than Malays (Bonferroni, P=0.002, P=0.042), and Chinese experiencing greater degree of doxorubicin-induced myelosuppression than Malays and Indians (post hoc Bonferroni, P=0.024 and 0.025). Genotyping revealed both PXR and CAR to be well conserved; only a PXR 5'-untranslated region polymorphism (-24381A>C) and a silent CAR variant (Pro180Pro) were found at allele frequencies of 26 and 53%, respectively. Two non-synonymous variants were identified in HNF4alpha (Met49Val and Thr130Ile) at allele frequencies of 55 and 1%, respectively, with the Met49Val variant associated with slower neutrophil recovery in docetaxel-treated patients (ANOVA, P=0.046). Interactions were observed between HNF4alpha Met49Val and CAR Pro180Pro, with patients who were wild type for both variants experiencing least docetaxel-induced neutropenia (ANOVA, P=0.030). No other significant genotypic associations with pharmacokinetics or pharmacodynamics of either drug were found. The PXR-24381A>C variants were significantly more common in Indians compared to Chinese or Malays (32/18/21%, P=0.035) Inter-individual and inter-ethnic variations of docetaxel and doxorubicin pharmacokinetics or pharmacodynamics exist, but genotypic variability of the transcriptional regulators PAR, CAR and HNF4alpha cannot account for this variability.
Hor
S Y
SY
Department of Biochemistry, National University of Singapore, Singapore.
Lee
S C
SC
Wong
C I
CI
Lim
Y W
YW
Lim
R C
RC
Wang
L Z
LZ
Fan
L
L
Guo
J Y
JY
Lee
H S
HS
Goh
B C
BC
Tan
T
T
D020121:5' Untranslated Regions; D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D044466:Asian People / Q000235:genetics*; D001792:Blood Platelets / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000208:ethnology / Q000235:genetics / Q000378:metabolism; D002681:China / Q000208:ethnology; D000090702:Constitutive Androstane Receptor; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D000077143:Docetaxel; D004317:Doxorubicin / Q000008:administration & dosage; D005091:Exons; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005787:Gene Frequency; D005838:Genotype; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007194:India / Q000208:ethnology; D008296:Malaysia / Q000208:ethnology; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced / Q000208:ethnology / Q000235:genetics; D011110:Polymorphism, Genetic; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism; D011987:Receptors, Steroid / Q000235:genetics* / Q000378:metabolism; D012846:Singapore / Q000453:epidemiology; D043823:Taxoids / Q000008:administration & dosage; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D016896:Treatment Outcome
D020121:5' Untranslated Regions; D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D000090702:Constitutive Androstane Receptor; C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D043823:Taxoids; D014157:Transcription Factors; D000077143:Docetaxel; D004317:Doxorubicin; D003577:Cytochrome P-450 Enzyme System; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A