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Impact of the haplotype CYP3A4*16B harboring the Thr185Ser substitution on paclitaxel metabolism in Japanese patients with cancer
Author(s) -
Nakajima Yukiko,
Yoshitani Takashi,
FukushimaUesaka Hiromi,
Saito Yoshiro,
Kaniwa Nahoko,
Kurose Kouichi,
Ozawa Shogo,
Aoyagi Nobuo,
Kamatani Naoyuki,
Yamamoto Noboru,
Kunitoh Hideo,
Ohe Yuichiro,
Tamura Tomohide,
Yoshida Teruhiko,
Minami Hironobu,
Saijo Nagahiro,
Katori Noriko,
Sawada Junichi
Publication year - 2006
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2006.04.012
Subject(s) - paclitaxel , pharmacokinetics , confidence interval , medicine , pharmacology , area under the curve , gastroenterology , oncology , haplotype , cancer , biology , allele , gene , genetics
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/m 2 , n = 199) than in the low‐dose group (≤100 mg/m 2 , 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 6α‐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 6α‐hydroxypaclitaxel. Clinical Pharmacology & Therapeutics (2006) 80 , 179–191; doi: 10.1016/j.clpt.2006.04.012