Impact of CYP3A4 haplotypes on irinotecan pharmacokinetics in Japanese cancer patients.
OBJECTIVE
Cytochrome P450 3A4 (CYP3A4) converts an anticancer prodrug, irinotecan, to inactive metabolites such as APC. However, the contribution of CYP3A4 genetic polymorphisms to irinotecan pharmacokinetics (PK) and pharmacodynamics (PD) is not fully elucidated. In paclitaxel-administered cancer patients, an association of CYP3A4*16B harboring the low activity allele *16 [554C > G (Thr185Ser)] has been shown with altered metabolite/paclitaxel area under the plasma concentration-time curve (AUC) ratios, suggesting a possible impact of *16B on the PK of other drugs. In this study, the effects of CYP3A4 haplotypes including *16B on irinotecan PK/PD were investigated in irinotecan-administered patients.


METHODS
The CYP3A4 genotypes for 177 Japanese cancer patients who received irinotecan were defined in terms of 4 major haplotypes, i.e., *1A (wild type), *1G (IVS10 + 12G > A), *16B [554C > G (Thr185Ser) and IVS10 + 12G > A], and *18B [878T > C (Leu293Pro) and IVS10 + 12G > A]. Associations of CYP3A4 genotypes with irinotecan PK and severe toxicities (grade 3 diarrhea and grade 3 or 4 neutropenia) were investigated.


RESULTS
Area under the concentration-time curve ratios of APC/irinotecan, an in vivo parameter for CYP3A4 activity, were significantly higher in females than in males. The male patients with *16B showed significantly decreased AUC ratios (APC/irinotecan) with 50% of the median value of the non-*16B male patients (no *16B-bearing female patients in this study), whereas no significant alteration in the AUC ratios was observed in the patients with *18B. A slight trend toward increasing AUC ratios (20%) was detected in both male and female patients bearing *1G. Multivariate analysis confirmed contributions of CYP3A4*16B (coefficient +/- SE = -0.18 +/- 0.077, P = 0.021) and *1G (0.047 +/- 0.021, P = 0.029) to the AUC ratio. However, no significant association was observed between the CYP3A4 genotypes and total clearance of irinotecan or toxicities (severe diarrhea and neutropenia).


CONCLUSIONS
This study suggested that CYP3A4*16B was associated with decreased metabolism of irinotecan to APC. However, the clinical impact of CYP3A4 genotypes on total clearance and irinotecan toxicities was not significant.
Sai
Kimie
K
Division of Biosignaling, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo, Japan. sai@nihs.go.jp
Saito
Yoshiro
Y
Fukushima-Uesaka
Hiromi
H
Kurose
Koichi
K
Kaniwa
Nahoko
N
Kamatani
Naoyuki
N
Shirao
Kuniaki
K
Yamamoto
Noboru
N
Hamaguchi
Tetsuya
T
Kunitoh
Hideo
H
Ohe
Yuichiro
Y
Tamura
Tomohide
T
Yamada
Yasuhide
Y
Minami
Hironobu
H
Ohtsu
Atsushi
A
Yoshida
Teruhiko
T
Saijo
Nagahiro
N
Sawada
Jun-ichi
J
D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D006239:Haplotypes; D006801:Humans; D000077146:Irinotecan; D007564:Japan; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D015999:Multivariate Analysis; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D011110:Polymorphism, Genetic; D011355:Prodrugs / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012737:Sex Factors
D000972:Antineoplastic Agents, Phytogenic; D011355:Prodrugs; C100720:RPR 121056; D000077146:Irinotecan; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D002166:Camptothecin