CYP2C19 polymorphism affects single-dose pharmacokinetics of oral pantoprazole in healthy volunteers |
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Authors: | Barbara Gawrońska-Szklarz Urszula Adamiak-Giera El?bieta Wyska Mateusz Kurzawski Wanda Gornik Maria Kaldonska Marek Drozdzik |
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Affiliation: | Department of Pharmacology, Pomeranian Medical University, Powstancow Wlkp 72, 70-111 Szczecin, Poland. |
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Abstract: | Objectives Pantoprazole is metabolized by cytochrome P450 2?C19, which shows genetic polymorphism. The effect of CYP2C19 polymorphism on single-dose pharmacokinetics of oral pantoprazole in healthy volunteers was evaluated. Methods Pantoprazole pharmacokinetics was determined in 32 healthy volunteers after a 40-mg single oral dose of the drug. Results Carriers of CYP2C19*2/*2 (n?=?2) were characterized by higher, starting from 3.5?h post dose, plasma concentrations of pantoprazole in comparison to wild-type (CYP2C19*1/*1, n?=?6) volunteers. In subjects with CYP2C19*17/*17 genotype (n?=?6) significantly lower plasma concentrations of the drug vs CYP2C19*1/*1 carriers, were observed from 3.0?h after oral pantoprazole administration. Carriers of CYP2C19*1/*17 (n?=?6) and CYP2C19*2/*17 (n?=?6) displayed concentration–time profiles comparable to wild-type subjects. CYP2C19*2/*2 volunteers showed a decrease in terminal elimination rate constant (λz) by 83.3%, prolongation of terminal half-life (t?) by 572%, a rise in area under the concentration–time curve (AUC) and mean residence time (MRT) by 506% and 259% respectively. Heterozygotes, i.e.. CYP2C19*1/*2 vs CYP2C19*1/*1 were characterized by higher AUC (4.38?±?1.00?mg?h/L vs 3.00?±?1.02 mg?h/L, p?0.05) and Cmax (2.13?±?0.42?mg/L vs 1.61?±?0.35?mg/L, p?0.05) respectively. A significant reduction in MRT (3.83?±?0.82?h vs 2.73?±?0.23?h, p?0.05) in carriers of CYP2C19*17/*17 vs CYP2C19*1/*1 genotypes was observed. Population modeling confirmed the influence of *1/*2, *2/*2, and *17/*17 genotypes on the pharmacokinetics of pantoprazole. The lowest population oral clearance was assessed in the carriers of genotype *2/*2 (3.68?L/h) and the highest value in subjects with genotype *17/*17 (31.13?L/h). Conclusion These data suggest that CYP2C19 polymorphism is an important determinant of pantoprazole pharmacokinetics. |
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