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1. Eur J Clin Pharmacol. 2012 Mar 15. [Epub ahead of print]

CYP2C19 polymorphism affects single-dose pharmacokinetics of oral pantoprazole in
healthy volunteers.

Gawrońska-Szklarz B, Adamiak-Giera U, Wyska E, Kurzawski M, Gornik W, Kaldonska
M, Drozdzik M.

Department of Pharmacology, Pomeranian Medical University, Powstancow Wlkp 72,
70-111, Szczecin, Poland.

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 (λ(z)) by 83.3%, prolongation of terminal half-life
(t(½)) 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[Symbol: see text]h/L vs 3.00 ± 1.02 mg[Symbol: see text]h/L,
p < 0.05) and C(max) (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.

PMID: 22418828 [PubMed - as supplied by publisher]