title: CYP2C8 haplotype structures and their influence on pharmacokinetics of paclitaxel in a Japanese population.
abstract: OBJECTIVE
  CYP2C8 is known to metabolize various drugs including an anticancer drug paclitaxel. Although large interindividual differences in CYP2C8 enzymatic activity and several nonsynonymous variations were reported, neither haplotype structures nor their associations with pharmacokinetic parameters of paclitaxel were reported.
  
  
  METHODS
  Haplotype structures of the CYP2C8 gene were inferred by an expectation-maximization based program using 40 genetic variations detected in 437 Japanese patients, which included cancer patients. Associations of the haplotypes and paclitaxel pharmacokinetic parameters were analyzed for 199 paclitaxel-administered cancer patients.
  
  
  RESULTS
  Relatively strong linkage disequilibriums were observed throughout the CYP2C8 gene. We estimated 40 haplotypes without an amino-acid change and nine haplotypes with amino acid changes. The 40 haplotypes were classified into six groups based on network analysis. The patients with heterozygous *IG group haplotypes harboring several intronic variations showed a 2.5-fold higher median area under concentration-time curve of C3'-p-hydroxy-paclitaxel and a 1.6-fold higher median value of C3'-p-hydroxy-paclitaxel/paclitaxel area under concentration-time curve ratio than patients bearing no *IG group haplotypes (P<0.001 for both comparisons by Mann-Whitney U-test). No statistically significant differences, however, were observed between patients with and without the *IG group (haplotypes) in clearance and area under concentration-time curve of paclitaxel, area under concentration-time curve of 6alpha-hydroxy-paclitaxel and 6alpha-, C3'-p-dihydroxy-paclitaxel, and area under concentration-time curve ratio of 6alpha-hydroxy-paclitaxel/paclitaxel.
  
  
  CONCLUSIONS
  CYP2C8*IG group haplotypes were associated with increased area under concentration-time curve of C3'-p-hydroxy-paclitaxel and area under concentration-time curve ratio of C3'-p-hydroxy-paclitaxel/paclitaxel. Thus, *IG group haplotypes might be associated with reduced CYP2C8 activity, possibly through its reduced protein levels.
authors.affiliation: Division of Biochemistry and Immunochemistry, National Institute of Health Sciences, Tokyo, Japan. yoshiro@nihs.go.jp
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Saito
authors.forename: Noriko
authors.initials: N
authors.lastname: Katori
authors.forename: Akiko
authors.initials: A
authors.lastname: Soyama
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Nakajima
authors.forename: Takashi
authors.initials: T
authors.lastname: Yoshitani
authors.forename: Su-Ryang
authors.initials: SR
authors.lastname: Kim
authors.forename: Hiromi
authors.initials: H
authors.lastname: Fukushima-Uesaka
authors.forename: Kouichi
authors.initials: K
authors.lastname: Kurose
authors.forename: Nahoko
authors.initials: N
authors.lastname: Kaniwa
authors.forename: Shogo
authors.initials: S
authors.lastname: Ozawa
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kamatani
authors.forename: Kazuo
authors.initials: K
authors.lastname: Komamura
authors.forename: Shiro
authors.initials: S
authors.lastname: Kamakura
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kitakaze
authors.forename: Hitonobu
authors.initials: H
authors.lastname: Tomoike
authors.forename: Kenji
authors.initials: K
authors.lastname: Sugai
authors.forename: Narihiro
authors.initials: N
authors.lastname: Minami
authors.forename: Hideo
authors.initials: H
authors.lastname: Kimura
authors.forename: Yu-ichi
authors.initials: Y
authors.lastname: Goto
authors.forename: Hironobu
authors.initials: H
authors.lastname: Minami
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Yoshida
authors.forename: Hideo
authors.initials: H
authors.lastname: Kunitoh
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Ohe
authors.forename: Noboru
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Tomohide
authors.initials: T
authors.lastname: Tamura
authors.forename: Nagahiro
authors.initials: N
authors.lastname: Saijo
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Sawada
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism*; D044466:Asian People / Q000235:genetics; D001483:Base Sequence; D065727:Cytochrome P-450 CYP2C8; D017931:DNA Primers / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D005828:Genetics, Population; D006239:Haplotypes; D006801:Humans; D007564:Japan; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D017239:Paclitaxel / Q000493:pharmacokinetics*; D010597:Pharmacogenetics
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D017931:DNA Primers; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D017239:Paclitaxel