Effects of CYP2C9 genetic polymorphisms on the pharmacokinetics of zafirlukast

Hyun Jee Lee; Young Hoon Kim; Se Hyung Kim; Choong Min Lee; Ae Yun Yang; Choon Gon Jang; Seok Yong Lee; Jung Woo Bae; Chang Ik Choi

doi:10.1007/s12272-016-0785-x

Effects of CYP2C9 genetic polymorphisms on the pharmacokinetics of zafirlukast

Hyun Jee Lee, Young Hoon Kim, Se Hyung Kim, Choong Min Lee, Ae Yun Yang, Choon Gon Jang, Seok Yong Lee, Jung Woo Bae, Chang Ik Choi

Research output: Contribution to journal › Article › peer-review

15 Scopus citations

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 C_max and AUC_inf 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 C_max 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.

Original language	English
Pages (from-to)	1013-1019
Number of pages	7
Journal	Archives of Pharmacal Research
Volume	39
Issue number	7
DOIs	https://doi.org/10.1007/s12272-016-0785-x
State	Published - 1 Jul 2016

Keywords

CYP2C9
Genetic polymorphism
Genotype
Pharmacokinetics
Zafirlukast

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10.1007/s12272-016-0785-x

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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.",

keywords = "CYP2C9, Genetic polymorphism, Genotype, Pharmacokinetics, Zafirlukast",

author = "Lee, {Hyun Jee} and Kim, {Young Hoon} and Kim, {Se Hyung} and Lee, {Choong Min} and Yang, {Ae Yun} and Jang, {Choon Gon} and Lee, {Seok Yong} and Bae, {Jung Woo} and Choi, {Chang Ik}",

note = "Publisher Copyright: {\textcopyright} 2016, The Pharmaceutical Society of Korea.",

year = "2016",

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day = "1",

doi = "10.1007/s12272-016-0785-x",

language = "English",

volume = "39",

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journal = "Archives of Pharmacal Research",

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TY - JOUR

T1 - Effects of CYP2C9 genetic polymorphisms on the pharmacokinetics of zafirlukast

AU - Lee, Hyun Jee

AU - Kim, Young Hoon

AU - Kim, Se Hyung

AU - Lee, Choong Min

AU - Yang, Ae Yun

AU - Jang, Choon Gon

AU - Lee, Seok Yong

AU - Bae, Jung Woo

AU - Choi, Chang Ik

PY - 2016/7/1

Y1 - 2016/7/1

N2 - 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.

AB - 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.

KW - CYP2C9

KW - Genetic polymorphism

KW - Genotype

KW - Pharmacokinetics

KW - Zafirlukast

UR - http://www.scopus.com/inward/record.url?scp=84976871021&partnerID=8YFLogxK

U2 - 10.1007/s12272-016-0785-x

DO - 10.1007/s12272-016-0785-x

M3 - Article

C2 - 27377818

AN - SCOPUS:84976871021

SN - 0253-6269

VL - 39

SP - 1013

EP - 1019

JO - Archives of Pharmacal Research

JF - Archives of Pharmacal Research

IS - 7

ER -

Effects of CYP2C9 genetic polymorphisms on the pharmacokinetics of zafirlukast

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