title: Effects of CYP2C9 genetic polymorphisms on the pharmacokinetics of zafirlukast.
abstract: Zafirlukast, a cysteinyl leukotriene receptor antagonist, is indicated for the treatment of patients with mild to moderate asthma. Zafirlukast is metabolized mainly by CYP3A4 and CYP2C9. We investigated the effects of the major CYP2C9 variant alleles in Asian populations, CYP2C9*3 and CYP2C9*13, on the pharmacokinetics of zafirlukast in healthy Korean subjects. A single 20-mg oral dose of zafirlukast was given to 23 Korean male subjects divided into two genotype groups according to CYP2C9 genotypes, CYP2C9EM (n = 11; CYP2C9*1/*1) and CYP2C9IM (n = 12; 9 and 3 carriers of CYP2C9*1/*3 and *1/*13, respectively). Zafirlukast concentrations were determined using a validated HPLC-MS/MS analytical method in plasma samples collected after the drug intake. Compared with the CYP2C9EM group, the Cmax and AUCinf of zafirlukast in the CYP2C9IM group were 1.44- and 1.70-fold higher, respectively (p < 0.01 and p < 0.0001). The CL/F of zafirlukast was 42.8 % lower in the CYP2C9IM group compared with the CYP2C9EM group (p < 0.001). Slightly higher Cmax and AUC, and lower CL/F of zafirlukast were observed in subjects with the CYP2C9*1/*13 genotype compared with the CYP2C9*1/*3 genotype subjects. CYP2C9*3 and CYP2C9*13 alleles significantly affected the plasma concentrations of zafirlukast.
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
authors.forename: Hyun-Jee
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
authors.forename: Young-Hoon
authors.initials: YH
authors.lastname: Kim
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
authors.forename: Se-Hyung
authors.initials: SH
authors.lastname: Kim
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
authors.forename: Choong-Min
authors.initials: CM
authors.lastname: Lee
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
authors.forename: Ae-Yun
authors.initials: AY
authors.lastname: Yang
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
authors.forename: Choon-Gon
authors.initials: CG
authors.lastname: Jang
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea. sylee@skku.ac.kr.
authors.forename: Seok-Yong
authors.initials: SY
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Keimyung University, Daegu, 42601, Republic of Korea.
authors.forename: Jung-Woo
authors.initials: JW
authors.lastname: Bae
authors.affiliation: College of Pharmacy, Dongguk University-Seoul, Goyang, 10326, Republic of Korea. cichoi@dongguk.edu.
authors.forename: Chang-Ik
authors.initials: CI
authors.lastname: Choi
mesh_terms: D000284:Administration, Oral; D000328:Adult; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D044466:Asian People / Q000235:genetics*; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007211:Indoles; D008297:Male; D048448:Phenylcarbamates; D011110:Polymorphism, Genetic / Q000187:drug effects / Q000235:genetics*; D013449:Sulfonamides; D014105:Tosyl Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D018927:Anti-Asthmatic Agents; D007211:Indoles; D048448:Phenylcarbamates; D013449:Sulfonamides; D014105:Tosyl Compounds; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; C062735:zafirlukast
keywords: CYP2C9; Genetic polymorphism; Genotype; Pharmacokinetics; Zafirlukast