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Effects of erythromycin on voriconazole pharmacokinetics and association with CYP2C19 polymorphism.

Shi HY, Yan J, Zhu WH, Yang GP, Tan ZR, Wu WH, Zhou G, Chen XP, Ouyang DS - Eur. J. Clin. Pharmacol. (2010)

Bottom Line: Periods were separated by a washout period of 14 days.C(max), AUC(0-24), and AUC(0-infinity) of voriconazole were increased significantly, while oral clearance of voriconazole was decreased significantly by erythromycin administration (p < 0.001, respectively).In addition, significant increases in AUC(0-24) and AUC(0-infinity) and decreases in oral clearance of voriconazole after erythromycin treatment were observed in CYP2C19 HEMs and PMs (p < 0.05, respectively), but not in CYP2C19 EMs. Both CYP2C19 genotypes and CYP3A4 inhibitor erythromycin can influence the plasma concentration of voriconazole, and erythromycin increases plasma concentration of voriconazole in a CYP2C19 genotype-dependent manner.

View Article: PubMed Central - PubMed

Affiliation: Pharmacogenetics Research Institute, Institute of Clinical Pharmacology, Central South University, 110# Xiangya Road, Changsha, Hunan, 410078, China.

ABSTRACT

Purpose: To assess the impacts of erythromycin on the pharmacokinetics of voriconazole and its association with CYP2C19 genotypes in healthy Chinese male subjects.

Methods: A single-center, open, crossover clinical study with two treatment phases was carried out. Eighteen healthy male volunteers, including 6 CYP2C19 homozygous extensive metabolizers (EMs, *1/*1), 6 heterozygous EMs (HEMs, *1/*2 or *1/*3), and 6 CYP2C19 poor metabolizers (PMs, *2/*2 or *2/*3), were enrolled in this study. A single oral dose of 200 mg voriconazole was administrated to all subjects after 3-day pretreatment with either 500 mg erythromycin or placebo three times daily. Periods were separated by a washout period of 14 days. Serial venous blood samples were collected, and plasma concentrations of voriconazole were determined by HPLC.

Results: C(max), AUC(0-24), and AUC(0-infinity) of voriconazole were increased significantly, while oral clearance of voriconazole was decreased significantly by erythromycin administration (p < 0.001, respectively). Compared with individuals with CYP2C19 PM genotypes, individuals with CYP2C19 EM and HEM genotypes showed significantly decreased T(½), AUC(0-24), AUC(0-infinity), and increased oral clearance of voriconazole (p < 0.05, respectively). In addition, significant increases in AUC(0-24) and AUC(0-infinity) and decreases in oral clearance of voriconazole after erythromycin treatment were observed in CYP2C19 HEMs and PMs (p < 0.05, respectively), but not in CYP2C19 EMs.

Conclusion: Both CYP2C19 genotypes and CYP3A4 inhibitor erythromycin can influence the plasma concentration of voriconazole, and erythromycin increases plasma concentration of voriconazole in a CYP2C19 genotype-dependent manner.

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Mean (± SD) voriconazole plasma concentration–time profile after single oral administration of 200 mg of voriconazole according to CYP2C19 genotypes in the placebo treatment phase. EMextensive metabolizers, HEM heterozygous extensive metabolizers, PM poor metabolizers
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Fig2: Mean (± SD) voriconazole plasma concentration–time profile after single oral administration of 200 mg of voriconazole according to CYP2C19 genotypes in the placebo treatment phase. EMextensive metabolizers, HEM heterozygous extensive metabolizers, PM poor metabolizers

Mentions: Plasma concentration–time curves of voriconazole according to CYP2C19 genotypes in the placebo-treated phase are shown in Fig. 2. Significant differences in T½, AUC0–24, , and oral clearance of voriconazole were observed among CYP2C19 genotypes (p < 0.05, Table 1). Compared with individuals with CYP2C19 PM genotypes, individuals with EM and HEM genotypes showed significantly decreased T½, AUC0–24, , and increased oral clearance of voriconazole (p < 0.05 respectively, Table 1). No significant difference in any of the pharmacokinetics parameters of voriconazole between EM and HEM genotypes was observed in the placebo-treated phase (Table 1).Fig. 2


Effects of erythromycin on voriconazole pharmacokinetics and association with CYP2C19 polymorphism.

Shi HY, Yan J, Zhu WH, Yang GP, Tan ZR, Wu WH, Zhou G, Chen XP, Ouyang DS - Eur. J. Clin. Pharmacol. (2010)

Mean (± SD) voriconazole plasma concentration–time profile after single oral administration of 200 mg of voriconazole according to CYP2C19 genotypes in the placebo treatment phase. EMextensive metabolizers, HEM heterozygous extensive metabolizers, PM poor metabolizers
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2957581&req=5

Fig2: Mean (± SD) voriconazole plasma concentration–time profile after single oral administration of 200 mg of voriconazole according to CYP2C19 genotypes in the placebo treatment phase. EMextensive metabolizers, HEM heterozygous extensive metabolizers, PM poor metabolizers
Mentions: Plasma concentration–time curves of voriconazole according to CYP2C19 genotypes in the placebo-treated phase are shown in Fig. 2. Significant differences in T½, AUC0–24, , and oral clearance of voriconazole were observed among CYP2C19 genotypes (p < 0.05, Table 1). Compared with individuals with CYP2C19 PM genotypes, individuals with EM and HEM genotypes showed significantly decreased T½, AUC0–24, , and increased oral clearance of voriconazole (p < 0.05 respectively, Table 1). No significant difference in any of the pharmacokinetics parameters of voriconazole between EM and HEM genotypes was observed in the placebo-treated phase (Table 1).Fig. 2

Bottom Line: Periods were separated by a washout period of 14 days.C(max), AUC(0-24), and AUC(0-infinity) of voriconazole were increased significantly, while oral clearance of voriconazole was decreased significantly by erythromycin administration (p < 0.001, respectively).In addition, significant increases in AUC(0-24) and AUC(0-infinity) and decreases in oral clearance of voriconazole after erythromycin treatment were observed in CYP2C19 HEMs and PMs (p < 0.05, respectively), but not in CYP2C19 EMs. Both CYP2C19 genotypes and CYP3A4 inhibitor erythromycin can influence the plasma concentration of voriconazole, and erythromycin increases plasma concentration of voriconazole in a CYP2C19 genotype-dependent manner.

View Article: PubMed Central - PubMed

Affiliation: Pharmacogenetics Research Institute, Institute of Clinical Pharmacology, Central South University, 110# Xiangya Road, Changsha, Hunan, 410078, China.

ABSTRACT

Purpose: To assess the impacts of erythromycin on the pharmacokinetics of voriconazole and its association with CYP2C19 genotypes in healthy Chinese male subjects.

Methods: A single-center, open, crossover clinical study with two treatment phases was carried out. Eighteen healthy male volunteers, including 6 CYP2C19 homozygous extensive metabolizers (EMs, *1/*1), 6 heterozygous EMs (HEMs, *1/*2 or *1/*3), and 6 CYP2C19 poor metabolizers (PMs, *2/*2 or *2/*3), were enrolled in this study. A single oral dose of 200 mg voriconazole was administrated to all subjects after 3-day pretreatment with either 500 mg erythromycin or placebo three times daily. Periods were separated by a washout period of 14 days. Serial venous blood samples were collected, and plasma concentrations of voriconazole were determined by HPLC.

Results: C(max), AUC(0-24), and AUC(0-infinity) of voriconazole were increased significantly, while oral clearance of voriconazole was decreased significantly by erythromycin administration (p < 0.001, respectively). Compared with individuals with CYP2C19 PM genotypes, individuals with CYP2C19 EM and HEM genotypes showed significantly decreased T(½), AUC(0-24), AUC(0-infinity), and increased oral clearance of voriconazole (p < 0.05, respectively). In addition, significant increases in AUC(0-24) and AUC(0-infinity) and decreases in oral clearance of voriconazole after erythromycin treatment were observed in CYP2C19 HEMs and PMs (p < 0.05, respectively), but not in CYP2C19 EMs.

Conclusion: Both CYP2C19 genotypes and CYP3A4 inhibitor erythromycin can influence the plasma concentration of voriconazole, and erythromycin increases plasma concentration of voriconazole in a CYP2C19 genotype-dependent manner.

Show MeSH
Related in: MedlinePlus