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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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Related in: MedlinePlus

Mean (± SD) voriconazole plasma concentration–time profile after single oral administration of 200 mg voriconazole in all 18 subjects with a 4-day treatment with placebo (squares) or erythromycin (black circles)
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Fig1: Mean (± SD) voriconazole plasma concentration–time profile after single oral administration of 200 mg voriconazole in all 18 subjects with a 4-day treatment with placebo (squares) or erythromycin (black circles)

Mentions: Figure 1 showed the plasma concentration–time curves of voriconazole with a 4-day treatment with erythromycin and placebo. Compared with the placebo-treated phase, the Cmax (2.36 ± 0.78 μg/mL vs 3.16 ± 0.76 μg/mL, p < 0.001), AUC0–24 (12.65 ± 10.15 μg·h/mL vs 18.97 ± 13.86 μg·h/mL, p < 0.001), (15.62 ± 15.11 μg·h/mL vs 23.63 ± 20.45 μg·h/mL, p < 0.001) of voriconazole was increased significantly in the erythromycin treated phase, while the CLoral/F of voriconazole was decreased significantly by 4-day erythromycin treatment (381 ± 244 mL/min vs 245 ± 171 mL/min, p < 0.001, Table 1). No significant difference in T½ and Tmax was observed between the placebo- and erythromycin-treated phases (Table 1).Fig. 1


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 voriconazole in all 18 subjects with a 4-day treatment with placebo (squares) or erythromycin (black circles)
© Copyright Policy
Related In: Results  -  Collection

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

Fig1: Mean (± SD) voriconazole plasma concentration–time profile after single oral administration of 200 mg voriconazole in all 18 subjects with a 4-day treatment with placebo (squares) or erythromycin (black circles)
Mentions: Figure 1 showed the plasma concentration–time curves of voriconazole with a 4-day treatment with erythromycin and placebo. Compared with the placebo-treated phase, the Cmax (2.36 ± 0.78 μg/mL vs 3.16 ± 0.76 μg/mL, p < 0.001), AUC0–24 (12.65 ± 10.15 μg·h/mL vs 18.97 ± 13.86 μg·h/mL, p < 0.001), (15.62 ± 15.11 μg·h/mL vs 23.63 ± 20.45 μg·h/mL, p < 0.001) of voriconazole was increased significantly in the erythromycin treated phase, while the CLoral/F of voriconazole was decreased significantly by 4-day erythromycin treatment (381 ± 244 mL/min vs 245 ± 171 mL/min, p < 0.001, Table 1). No significant difference in T½ and Tmax was observed between the placebo- and erythromycin-treated phases (Table 1).Fig. 1

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