Pharmacogenetics and Genomics
Clinical Pharmacology & Therapeutics (2006) 80, 179–191; doi: 10.1016/j.clpt.2006.04.012
Impact of the haplotype CYP3A4*16B harboring the Thr185Ser substitution on paclitaxel metabolism in Japanese patients with cancer*
Yukiko Nakajima PhD1,*, Takashi Yoshitani PhD1,*, Hiromi Fukushima-Uesaka MSc1,*, Yoshiro Saito PhD1, Nahoko Kaniwa PhD1, Kouichi Kurose PhD1, Shogo Ozawa PhD1, Nobuo Aoyagi PhD1, Naoyuki Kamatani MD, PhD1, Noboru Yamamoto MD1, Hideo Kunitoh MD1, Yuichiro Ohe MD1, Tomohide Tamura MD1, Teruhiko Yoshida MD1, Hironobu Minami MD1, Nagahiro Saijo MD1, Noriko Katori PhD1 and Jun-ichi Sawada PhD1
1National Institute of Health Sciences, Tokyo Women's Medical University, National Cancer Center Hospital, and National Cancer Center Research Institute, Tokyo, Japan, and National Cancer Center Hospital East, Chiba, Japan.
Correspondence: Noriko Katori, PhD, Project Team for Pharmacogenetics, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan. E-mail: katori@nihs.go.jp
*Drs Nakajima, Yoshitani, and Fukushima-Uesaka contributed equally to this work.
*Supported in part by the Program for Promotion of Fundamental Studies in Health Sciences and by a grant from the Japan Health Sciences Foundation.
Received 22 December 2005; Accepted 19 April 2006.
Abstract
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 (
175 mg/m2, n = 199) than in the low-dose group (
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 6
-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 CYP3A4*16B is associated with both reduced 3'-p-hydroxylation of paclitaxel and probably increased levels of 6-hydroxypaclitaxel.
