title: Genetic variations of orosomucoid genes associated with serum alpha-1-acid glycoprotein level and the pharmacokinetics of paclitaxel in Japanese cancer patients.
abstract: Alpha-1-acid glycoprotein (AGP) encoded by orosomucoid genes (ORM1 and ORM2) is an acute-phase response protein and functions as a drug-binding protein that affects pharmacokinetics (PK)/pharmacodynamics of binding drugs. To explore the effects of genetic variations of ORMs and a role of AGP on paclitaxel (PTX) therapy, we analyzed the duplication and genetic variations/haplotypes of ORMs in 165 Japanese cancer patients and then investigated their associations with serum AGP levels and the PK parameters of PTX. No effects of ORM duplications on serum AGP levels at baseline or PK of PTX were observed, but close associations of ORM1 -559T > A with the increases of AGP levels and area under the curve (AUC) of PTX metabolites were detected. In addition, a significant correlation between the serum AGP level and the AUCs of PTX metabolites was observed, suggesting that AGP may function as a carrier of PTX from the blood into the liver via putative receptors. This study provided useful information on the possible clinical importance of ORM genetic polymorphisms and a novel role of AGP in PTX therapy.
authors.affiliation: National Institute of Health Sciences, Tokyo 158-8501, Japan. katori@nihs.go.jp.
authors.forename: Noriko
authors.initials: N
authors.lastname: Katori
authors.forename: Kimie
authors.initials: K
authors.lastname: Sai
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Saito
authors.forename: Hiromi
authors.initials: H
authors.lastname: Fukushima-Uesaka
authors.forename: Kouichi
authors.initials: K
authors.lastname: Kurose
authors.forename: Chikako
authors.initials: C
authors.lastname: Yomota
authors.forename: Toru
authors.initials: T
authors.lastname: Kawanishi
authors.forename: Tomoko
authors.initials: T
authors.lastname: Nishimaki-Mogami
authors.forename: Mikihiko
authors.initials: M
authors.lastname: Naito
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Sawada
authors.forename: Hideo
authors.initials: H
authors.lastname: Kunitoh
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nokihara
authors.forename: Ikuo
authors.initials: I
authors.lastname: Sekine
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Ohe
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Yoshida
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Matsumura
authors.forename: Nagahiro
authors.initials: N
authors.lastname: Saijo
authors.forename: Noboru
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Haruhiro
authors.initials: H
authors.lastname: Okuda
authors.forename: Tomohide
authors.initials: T
authors.lastname: Tamura
mesh_terms: D020121:5' Untranslated Regions; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D044466:Asian People / Q000235:genetics*; D005091:Exons; D005260:Female; D018628:Gene Dosage; D014644:Genetic Variation; D006239:Haplotypes; D065669:Hepatobiliary Elimination; D006801:Humans; D007564:Japan / Q000453:epidemiology; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000208:ethnology / Q000235:genetics; D009961:Orosomucoid / Q000235:genetics* / Q000378:metabolism*; D017239:Paclitaxel / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010597:Pharmacogenetics; D010641:Phenotype
chemical_list: D020121:5' Untranslated Regions; D000972:Antineoplastic Agents, Phytogenic; C573095:ORM2 protein, human; D009961:Orosomucoid; D017239:Paclitaxel