Effects of CYP2C9 genetic polymorphism on the pharmacokinetics of zafirlukast

Purpose: Zafirlukast is an oral leukotriene receptor antagonist (LTRA) for the maintenance treatment of asthma, often used in conjunction with an inhaled steroid and/or long-acting bronchodilator. A previous in vitro study showed that cytochrome P450 (CYP) 2C9 and 3A4 are the major enzymes participating in zafirlukast metabolism. It is reported that the CYP2C9*3 and CYP2C9*13 alleles are associated with decreased CYP2C9 enzyme activity. We investigated the effects of CYP2C9 genetic variants on the pharmacokinetics of zafirlukast.

Methods: Eighteen subjects were selected and they were divided into two different groups according to CYP2C9 genotype, CYP2C9EM (CYP2C9*1/*1, n=10) and CYP2C9IM (CYP2C19*1/*3, n=8). After overnight fasting, each subject received a single oral dose of 20 mg zafirlukast. Blood samples were collected up to 12 hr after drug intake, and plasma concentrations of zafirlukast were determined by a validated LC-MS/MS analytical method.

Results: C_max of zafirlukast in CYP2C9IM group was 1.4-fold higher than that in CYP2C9EM group (397.8±87.5 ng/mL vs. 290.7±57.6 ng/mL, P<0.01). AUC_inf of zafirlukast in CYP2C9IM group was also 1.6-fold higher than that in CYP2C9EM group (1244.3±205.2 ng·hr/mL vs. 768.1±135.2 ng·hr/mL, P<0.0001). Apparent oral clearance (CL/F) of zafirlukast in CYP2C9IM group was 39% lower than that in CYP2C9EM group (16.5±2.9 L/hr vs. 27.0±4.9 L/hr, P<0.0001).

Conclusion: CYP2C9 genetic polymorphism significantly affected the pharmacokinetics of zafirlukast.