title: Irinotecan pharmacokinetics/pharmacodynamics and UGT1A genetic polymorphisms in Japanese: roles of UGT1A1*6 and *28.
abstract: OBJECTIVE
  SN-38, an active metabolite of irinotecan, is detoxified by glucuronidation with UGT1A isoforms, 1A1, 1A7, 1A9, and 1A10. The pharmacogenetic information on UGT1A haplotypes covering all these isoforms is important for the individualized therapy of irinotecan. Associations between UGT1A haplotypes and pharmacokinetics/pharmacodynamics of irinotecan were investigated to identify pharmacogenetic markers.
  
  
  METHODS
  Associations between UGT1A haplotypes and the area under concentration curve ratio (SN-38 glucuronide/SN-38) or toxicities were analyzed in 177 Japanese cancer patients treated with irinotecan as a single agent or in combination chemotherapy. For association analysis, diplotypes of UGT1A gene segments [(1A1, 1A7, 1A9, 1A10), and Block C (common exons 2-5)] and combinatorial haplotypes (1A9-1A7-1A1) were used. The relationship between diplotypes and toxicities was investigated in 55 patients treated with irinotecan as a single agent.
  
  
  RESULTS
  Among diplotypes of UGT1A genes, patients with the haplotypes harboring UGT1A1*6 or *28 had significantly reduced area under concentration curve ratios, with the effects of UGT1A1*6 or *28 being of a similar scale. A gene dose effect on the area under concentration curve ratio was observed for the number of haplotypes containing *28 or *6 (5.55, 3.62, and 2.07 for 0, 1, and 2 haplotypes, respectively, P<0.0001). In multivariate analysis, the homozygotes and double heterozygotes of *6 and *28 (*6/*6, *28/*28 and *6/*28) were significantly associated with severe neutropenia in 53 patients who received irinotecan monotherapy.
  
  
  CONCLUSIONS
  The haplotypes significantly associated with reduced area under concentration curve ratios and neutropenia contained UGT1A1*6 or *28, and both of them should be genotyped before irinotecan is given to Japanese and probably other Asian patients.
authors.affiliation: Division of Oncology, National Cancer Center Hospital East, Kashiwa, Japan. hminami@east.ncc.go.jp
authors.forename: Hironobu
authors.initials: H
authors.lastname: Minami
authors.forename: Kimie
authors.initials: K
authors.lastname: Sai
authors.forename: Mayumi
authors.initials: M
authors.lastname: Saeki
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Saito
authors.forename: Shogo
authors.initials: S
authors.lastname: Ozawa
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Suzuki
authors.forename: Nahoko
authors.initials: N
authors.lastname: Kaniwa
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Sawada
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Hamaguchi
authors.forename: Noboru
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Shirao
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Yamada
authors.forename: Hironobu
authors.initials: H
authors.lastname: Ohmatsu
authors.forename: Kaoru
authors.initials: K
authors.lastname: Kubota
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Yoshida
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ohtsu
authors.forename: Nagahiro
authors.initials: N
authors.lastname: Saijo
mesh_terms: D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D044466:Asian People / Q000235:genetics; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D005091:Exons; D005260:Female; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism*; D006239:Haplotypes; D006801:Humans; D000077146:Irinotecan; D007564:Japan; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D011355:Prodrugs / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D000099148:UGT1A1 Enzyme
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D002166:Camptothecin; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D011355:Prodrugs; D000099148:UGT1A1 Enzyme