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Effects of CYP2C9 genetic polymorphisms on the pharmacokinetics of zafirlukast

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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.

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Acknowledgments

This work was supported by the NRF grant funded by the Korea government (MSIP) (No. 2016R1A2B4007381).

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    Authors and Affiliations

    1. School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea

      Hyun-Jee Lee, Young-Hoon Kim, Se-Hyung Kim, Choong-Min Lee, Ae-Yun Yang, Choon-Gon Jang & Seok-Yong Lee

    2. College of Pharmacy, Keimyung University, Daegu, 42601, Republic of Korea

      Jung-Woo Bae

    3. College of Pharmacy, Dongguk University-Seoul, Goyang, 10326, Republic of Korea

      Chang-Ik Choi

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    1. Hyun-Jee Lee
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    Hyun-Jee Lee, Young-Hoon Kim, and Se-Hyung Kim, have contributed equally to this study.

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    Lee, HJ., Kim, YH., Kim, SH. et al. Effects of CYP2C9 genetic polymorphisms on the pharmacokinetics of zafirlukast. Arch. Pharm. Res. 39, 1013–1019 (2016). https://doi.org/10.1007/s12272-016-0785-x

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