Effects of fluconazole on the pharmacokinetics of celecoxib and its carboxylic acid metabolite in different CYP2C9 genotypes

This study aimed to investigate the effects of fluconazole, a moderate inhibitor of CYP2C9 and CYP3A4, on the pharmacokinetics of celecoxib and its carboxylic acid metabolite in different CYP2C9 genotypes. A total of thirty-nine healthy Korean male volunteers were divided into three different CYP2C9...

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Veröffentlicht in:Archives of pharmacal research Jg. 48; H. 3; S. 224 - 233
Hauptverfasser: Cho, Chang-Keun, Kang, Pureum, Jang, Choon-Gon, Lee, Yun Jeong, Bae, Jung-Woo, Choi, Chang-Ik, Lee, Seok-Yong
Format: Journal Article
Sprache:Englisch
Veröffentlicht: Seoul Pharmaceutical Society of Korea 01.03.2025
대한약학회
Schlagworte:
Administration, Oral
Adult
Antifungal Agents - administration & dosage
Antifungal Agents - pharmacology
carboxylic acids
Carboxylic Acids - metabolism
Carboxylic Acids - pharmacokinetics
Celecoxib - administration & dosage
Celecoxib - blood
Celecoxib - pharmacokinetics
Cyclooxygenase 2 Inhibitors - administration & dosage
Cyclooxygenase 2 Inhibitors - pharmacokinetics
Cytochrome P-450 CYP2C9 - genetics
Cytochrome P-450 CYP2C9 - metabolism
Drug Interactions
fluconazole
Fluconazole - administration & dosage
Fluconazole - pharmacology
Genotype
Healthy Volunteers
Humans
Male
males
Medicine
metabolites
oral administration
pharmacokinetics
Pharmacology/Toxicology
Pharmacy
Research Article
Young Adult
약학
CYP2C9
Genotype
Celecoxib
Fluconazole
Pharmacokinetics
Celecoxib carboxylic acid
ISSN:0253-6269, 1976-3786, 1976-3786
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Abstract This study aimed to investigate the effects of fluconazole, a moderate inhibitor of CYP2C9 and CYP3A4, on the pharmacokinetics of celecoxib and its carboxylic acid metabolite in different CYP2C9 genotypes. A total of thirty-nine healthy Korean male volunteers were divided into three different CYP2C9 genotype groups ( CYP2C9*1/*1 , *1/*3 and *3/*3 genotypes) and were enrolled in the celecoxib alone trial, celecoxib with fluconazole trial, or both. In the celecoxib alone trial, participants received a single oral dose of 200 mg celecoxib. In the celecoxib with fluconazole trial, participants received 300 mg fluconazole on day 1, 150 mg fluconazole once daily for four consecutive days (day 2–5), and a coadministration of 200 mg celecoxib with 150 mg fluconazole on day 6. Plasma concentrations of celecoxib and celecoxib carboxylic acid were determined by using HPLC–MS/MS. In the CYP2C9*1/*1 genotype group, fluconazole treatment increased AUC inf of celecoxib by 2.61-fold, and decreased CL/F by 60.4% (both p < 0.001). In the CYP2C9*1/*3 genotype group, fluconazole treatment increased AUC inf of celecoxib by 2.44-fold (p < 0.001), prolonged t 1/2 by 1.36-fold (p < 0.05), and decreased CL/F by 60.4% (p < 0.001). Fluconazole treatment increased AUC inf of celecoxib by 2.23-fold, prolonged t 1/2 by 1.64-fold, and decreased CL/F by 53.8% in the subject with CYP2C9*3/*3 genotype. C max of celecoxib carboxylic acid significantly decreased in CYP2C9*1/*1 and *1/*3 genotypes (p < 0.01 and p < 0.05, respectively), following fluconazole treatment, whereas AUC inf showed no significant changes in any CYP2C9 genotype group. In conclusion, fluconazole affected the pharmacokinetics of celecoxib in different CYP2C9 genotypes.
AbstractList This study aimed to investigate the effects of fluconazole, a moderate inhibitor of CYP2C9 and CYP3A4, on the pharmacokinetics of celecoxib and its carboxylic acid metabolite in different CYP2C9 genotypes. A total of thirty-nine healthy Korean male volunteers were divided into three different CYP2C9 genotype groups (CYP2C9*1/*1, *1/*3 and *3/*3 genotypes) and were enrolled in the celecoxib alone trial, celecoxib with fluconazole trial, or both. In the celecoxib alone trial, participants received a single oral dose of 200 mg celecoxib. In the celecoxib with fluconazole trial, participants received 300 mg fluconazole on day 1, 150 mg fluconazole once daily for four consecutive days (day 2-5), and a coadministration of 200 mg celecoxib with 150 mg fluconazole on day 6. Plasma concentrations of celecoxib and celecoxib carboxylic acid were determined by using HPLC-MS/MS. In the CYP2C9*1/*1 genotype group, fluconazole treatment increased AUCinf of celecoxib by 2.61-fold, and decreased CL/F by 60.4% (both p < 0.001). In the CYP2C9*1/*3 genotype group, fluconazole treatment increased AUCinf of celecoxib by 2.44-fold (p < 0.001), prolonged t1/2 by 1.36-fold (p < 0.05), and decreased CL/F by 60.4% (p < 0.001). Fluconazole treatment increased AUCinf of celecoxib by 2.23-fold, prolonged t1/2 by 1.64-fold, and decreased CL/F by 53.8% in the subject with CYP2C9*3/*3 genotype. Cmax of celecoxib carboxylic acid significantly decreased in CYP2C9*1/*1 and *1/*3 genotypes (p < 0.01 and p < 0.05, respectively), following fluconazole treatment, whereas AUCinf showed no significant changes in any CYP2C9 genotype group. In conclusion, fluconazole affected the pharmacokinetics of celecoxib in different CYP2C9 genotypes.This study aimed to investigate the effects of fluconazole, a moderate inhibitor of CYP2C9 and CYP3A4, on the pharmacokinetics of celecoxib and its carboxylic acid metabolite in different CYP2C9 genotypes. A total of thirty-nine healthy Korean male volunteers were divided into three different CYP2C9 genotype groups (CYP2C9*1/*1, *1/*3 and *3/*3 genotypes) and were enrolled in the celecoxib alone trial, celecoxib with fluconazole trial, or both. In the celecoxib alone trial, participants received a single oral dose of 200 mg celecoxib. In the celecoxib with fluconazole trial, participants received 300 mg fluconazole on day 1, 150 mg fluconazole once daily for four consecutive days (day 2-5), and a coadministration of 200 mg celecoxib with 150 mg fluconazole on day 6. Plasma concentrations of celecoxib and celecoxib carboxylic acid were determined by using HPLC-MS/MS. In the CYP2C9*1/*1 genotype group, fluconazole treatment increased AUCinf of celecoxib by 2.61-fold, and decreased CL/F by 60.4% (both p < 0.001). In the CYP2C9*1/*3 genotype group, fluconazole treatment increased AUCinf of celecoxib by 2.44-fold (p < 0.001), prolonged t1/2 by 1.36-fold (p < 0.05), and decreased CL/F by 60.4% (p < 0.001). Fluconazole treatment increased AUCinf of celecoxib by 2.23-fold, prolonged t1/2 by 1.64-fold, and decreased CL/F by 53.8% in the subject with CYP2C9*3/*3 genotype. Cmax of celecoxib carboxylic acid significantly decreased in CYP2C9*1/*1 and *1/*3 genotypes (p < 0.01 and p < 0.05, respectively), following fluconazole treatment, whereas AUCinf showed no significant changes in any CYP2C9 genotype group. In conclusion, fluconazole affected the pharmacokinetics of celecoxib in different CYP2C9 genotypes.
This study aimed to investigate the effects of fluconazole, a moderate inhibitor of CYP2C9 and CYP3A4, on the pharmacokinetics of celecoxib and its carboxylic acid metabolite in different CYP2C9 genotypes. A total of thirty-nine healthy Korean male volunteers were divided into three different CYP2C9 genotype groups (CYP2C9*1/*1, *1/*3 and *3/*3 genotypes) and were enrolled in the celecoxib alone trial, celecoxib with fluconazole trial, or both. In the celecoxib alone trial, participants received a single oral dose of 200 mg celecoxib. In the celecoxib with fluconazole trial, participants received 300 mg fluconazole on day 1, 150 mg fluconazole once daily for four consecutive days (day 2-5), and a coadministration of 200 mg celecoxib with 150 mg fluconazole on day 6. Plasma concentrations of celecoxib and celecoxib carboxylic acid were determined by using HPLC-MS/MS. In the CYP2C9*1/*1 genotype group, fluconazole treatment increased AUC of celecoxib by 2.61-fold, and decreased CL/F by 60.4% (both p < 0.001). In the CYP2C9*1/*3 genotype group, fluconazole treatment increased AUC of celecoxib by 2.44-fold (p < 0.001), prolonged t by 1.36-fold (p < 0.05), and decreased CL/F by 60.4% (p < 0.001). Fluconazole treatment increased AUC of celecoxib by 2.23-fold, prolonged t by 1.64-fold, and decreased CL/F by 53.8% in the subject with CYP2C9*3/*3 genotype. C of celecoxib carboxylic acid significantly decreased in CYP2C9*1/*1 and *1/*3 genotypes (p < 0.01 and p < 0.05, respectively), following fluconazole treatment, whereas AUC showed no significant changes in any CYP2C9 genotype group. In conclusion, fluconazole affected the pharmacokinetics of celecoxib in different CYP2C9 genotypes.
This study aimed to investigate the effects of fluconazole, a moderate inhibitor of CYP2C9 and CYP3A4, on the pharmacokinetics of celecoxib and its carboxylic acid metabolite in different CYP2C9 genotypes. A total of thirty-nine healthy Korean male volunteers were divided into three different CYP2C9 genotype groups ( CYP2C9*1/*1 , *1/*3 and *3/*3 genotypes) and were enrolled in the celecoxib alone trial, celecoxib with fluconazole trial, or both. In the celecoxib alone trial, participants received a single oral dose of 200 mg celecoxib. In the celecoxib with fluconazole trial, participants received 300 mg fluconazole on day 1, 150 mg fluconazole once daily for four consecutive days (day 2–5), and a coadministration of 200 mg celecoxib with 150 mg fluconazole on day 6. Plasma concentrations of celecoxib and celecoxib carboxylic acid were determined by using HPLC–MS/MS. In the CYP2C9*1/*1 genotype group, fluconazole treatment increased AUC inf of celecoxib by 2.61-fold, and decreased CL/F by 60.4% (both p < 0.001). In the CYP2C9*1/*3 genotype group, fluconazole treatment increased AUC inf of celecoxib by 2.44-fold (p < 0.001), prolonged t 1/2 by 1.36-fold (p < 0.05), and decreased CL/F by 60.4% (p < 0.001). Fluconazole treatment increased AUC inf of celecoxib by 2.23-fold, prolonged t 1/2 by 1.64-fold, and decreased CL/F by 53.8% in the subject with CYP2C9*3/*3 genotype. C max of celecoxib carboxylic acid significantly decreased in CYP2C9*1/*1 and *1/*3 genotypes (p < 0.01 and p < 0.05, respectively), following fluconazole treatment, whereas AUC inf showed no significant changes in any CYP2C9 genotype group. In conclusion, fluconazole affected the pharmacokinetics of celecoxib in different CYP2C9 genotypes.
This study aimed to investigate the effects of fluconazole, a moderate inhibitor of CYP2C9 and CYP3A4, on the pharmacokinetics of celecoxib and its carboxylic acid metabolite in different CYP2C9 genotypes. A total of thirty-nine healthy Korean male volunteers were divided into three different CYP2C9 genotype groups (CYP2C9*1/*1, *1/*3 and *3/*3 genotypes) and were enrolled in the celecoxib alone trial, celecoxib with fluconazole trial, or both. In the celecoxib alone trial, participants received a single oral dose of 200 mg celecoxib. In the celecoxib with fluconazole trial, participants received 300 mg fluconazole on day 1, 150 mg fluconazole once daily for four consecutive days (day 2–5), and a coadministration of 200 mg celecoxib with 150 mg fluconazole on day 6. Plasma concentrations of celecoxib and celecoxib carboxylic acid were determined by using HPLC–MS/MS. In the CYP2C9*1/*1 genotype group, fluconazole treatment increased AUCinf of celecoxib by 2.61-fold, and decreased CL/F by 60.4% (both p < 0.001). In the CYP2C9*1/*3 genotype group, fluconazole treatment increased AUCinf of celecoxib by 2.44-fold (p < 0.001), prolonged t1/2 by 1.36-fold (p < 0.05), and decreased CL/F by 60.4% (p < 0.001). Fluconazole treatment increased AUCinf of celecoxib by 2.23-fold, prolonged t1/2 by 1.64-fold, and decreased CL/F by 53.8% in the subject with CYP2C9*3/*3 genotype. Cmax of celecoxib carboxylic acid significantly decreased in CYP2C9*1/*1 and *1/*3 genotypes (p < 0.01 and p < 0.05, respectively), following fluconazole treatment, whereas AUCinf showed no significant changes in any CYP2C9 genotype group. In conclusion, fluconazole affected the pharmacokinetics of celecoxib in different CYP2C9 genotypes. KCI Citation Count: 0
This study aimed to investigate the effects of fluconazole, a moderate inhibitor of CYP2C9 and CYP3A4, on the pharmacokinetics of celecoxib and its carboxylic acid metabolite in different CYP2C9 genotypes. A total of thirty-nine healthy Korean male volunteers were divided into three different CYP2C9 genotype groups (CYP2C9*1/*1, *1/*3 and *3/*3 genotypes) and were enrolled in the celecoxib alone trial, celecoxib with fluconazole trial, or both. In the celecoxib alone trial, participants received a single oral dose of 200 mg celecoxib. In the celecoxib with fluconazole trial, participants received 300 mg fluconazole on day 1, 150 mg fluconazole once daily for four consecutive days (day 2–5), and a coadministration of 200 mg celecoxib with 150 mg fluconazole on day 6. Plasma concentrations of celecoxib and celecoxib carboxylic acid were determined by using HPLC–MS/MS. In the CYP2C9*1/*1 genotype group, fluconazole treatment increased AUCᵢₙf of celecoxib by 2.61-fold, and decreased CL/F by 60.4% (both p < 0.001). In the CYP2C9*1/*3 genotype group, fluconazole treatment increased AUCᵢₙf of celecoxib by 2.44-fold (p < 0.001), prolonged t₁/₂ by 1.36-fold (p < 0.05), and decreased CL/F by 60.4% (p < 0.001). Fluconazole treatment increased AUCᵢₙf of celecoxib by 2.23-fold, prolonged t₁/₂ by 1.64-fold, and decreased CL/F by 53.8% in the subject with CYP2C9*3/*3 genotype. Cₘₐₓ of celecoxib carboxylic acid significantly decreased in CYP2C9*1/*1 and *1/*3 genotypes (p < 0.01 and p < 0.05, respectively), following fluconazole treatment, whereas AUCᵢₙf showed no significant changes in any CYP2C9 genotype group. In conclusion, fluconazole affected the pharmacokinetics of celecoxib in different CYP2C9 genotypes.
Author Cho, Chang-Keun
Jang, Choon-Gon
Lee, Yun Jeong
Kang, Pureum
Bae, Jung-Woo
Choi, Chang-Ik
Lee, Seok-Yong
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Keywords CYP2C9
Genotype
Celecoxib
Fluconazole
Pharmacokinetics
Celecoxib carboxylic acid
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Snippet This study aimed to investigate the effects of fluconazole, a moderate inhibitor of CYP2C9 and CYP3A4, on the pharmacokinetics of celecoxib and its carboxylic...
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SubjectTerms Administration, Oral
Adult
Antifungal Agents - administration & dosage
Antifungal Agents - pharmacology
carboxylic acids
Carboxylic Acids - metabolism
Carboxylic Acids - pharmacokinetics
Celecoxib - administration & dosage
Celecoxib - blood
Celecoxib - pharmacokinetics
Cyclooxygenase 2 Inhibitors - administration & dosage
Cyclooxygenase 2 Inhibitors - pharmacokinetics
Cytochrome P-450 CYP2C9 - genetics
Cytochrome P-450 CYP2C9 - metabolism
Drug Interactions
fluconazole
Fluconazole - administration & dosage
Fluconazole - pharmacology
Genotype
Healthy Volunteers
Humans
Male
males
Medicine
metabolites
oral administration
pharmacokinetics
Pharmacology/Toxicology
Pharmacy
Research Article
Young Adult
약학
Title Effects of fluconazole on the pharmacokinetics of celecoxib and its carboxylic acid metabolite in different CYP2C9 genotypes
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