Impact of the haplotype CYP3A4*16B harboring the Thr185Ser substitution on paclitaxel metabolism in Japanese patients with cancer.
OBJECTIVE
Paclitaxel is one of the most important anticancer drugs for the treatment of various tumors such as non-small cell lung cancer. We investigated the association between CYP3A4 haplotypes and pharmacokinetic parameters of paclitaxel metabolism.


METHODS
This study enrolled 235 Japanese patients with cancer who were receiving paclitaxel. These patients were screened for CYP3A4 gene polymorphisms by either direct sequencing or pyrosequencing. Plasma concentrations of paclitaxel and its 3 metabolites were determined by HPLC in 229 patients.


RESULTS
Median values of paclitaxel clearance, normalized for body surface area, were lower in the high-dose group (>or=175 mg/m2, n = 199) than in the low-dose group (<or=100 mg/m2, n = 30), suggesting nonlinearity of pharmacokinetics caused by Cremophor EL. Therefore we mainly used the patients in the high-dose group for further analysis. The median value of the area under the curve (AUC) ratio of 3'-p-hydroxypaclitaxel to paclitaxel was 20% greater (95% confidence interval, 2.4% to 41.7%) in the women than in the men (P = .01). Although no significant difference in paclitaxel clearance was observed among the CYP3A4 haplotypes, 16B-bearing (1/16B) patients (n = 8) showed a 20% lower (95% confidence interval, -58.5 to -11.5%) median AUC ratio of 3'-p-hydroxypaclitaxel to paclitaxel (P = .04) and a 2.4-fold higher median AUC ratio of 6alpha-hydroxypaclitaxel to paclitaxel (P < .001) compaed with those in the wild-type (1/1) patients (n = 180). In contrast, no significant differences were seen between 1/1 and 18B/1 (n = 10) patients for the pharmacokinetic parameters examined.


CONCLUSIONS
Our results suggest that CYP3A416B is associated with both reduced 3'-p-hydroxylation of paclitaxel and probably increased levels of 6alpha-hydroxypaclitaxel.
Nakajima
Yukiko
Y
National Institute of Health Sciences, Tokyo Women's Medical University, National Cancer Center Hospital, Japan.
Yoshitani
Takashi
T
Fukushima-Uesaka
Hiromi
H
Saito
Yoshiro
Y
Kaniwa
Nahoko
N
Kurose
Kouichi
K
Ozawa
Shogo
S
Aoyagi
Nobuo
N
Kamatani
Naoyuki
N
Yamamoto
Noboru
N
Kunitoh
Hideo
H
Ohe
Yuichiro
Y
Tamura
Tomohide
T
Yoshida
Teruhiko
T
Minami
Hironobu
H
Saijo
Nagahiro
N
Katori
Noriko
N
Sawada
Jun-ichi
J
D000328:Adult; D019943:Amino Acid Substitution; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics*; D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D004247:DNA / Q000235:genetics; D005079:Excipients; D005260:Female; D006239:Haplotypes; D006801:Humans; D007564:Japan; D008297:Male; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism*; D017239:Paclitaxel / Q000493:pharmacokinetics*; D011092:Polyethylene Glycols; D011110:Polymorphism, Genetic / Q000235:genetics; D012313:RNA; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000972:Antineoplastic Agents, Phytogenic; D005079:Excipients; C034477:RNA primers; C022131:cremophor; D011092:Polyethylene Glycols; D012313:RNA; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D017239:Paclitaxel