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Effects of CYP2C19 Genetic Polymorphisms on PK/PD Responses of Omeprazole in Korean Healthy Volunteers

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ABSTRACT

The aim of this study was to examine the effects of CYP2C19*2 and *3 genetic polymorphisms on omeprazole pharmacokinetic (PK) and pharmacodynamic (PD) responses. Twenty-four healthy Korean volunteers were enrolled and given 20 mg omeprazole orally once daily for 8 days. The genotypes of CYP2C19 single nucleotide polymorphisms (SNPs) (*2, *3, and *17) were screened. The plasma concentrations of omeprazole, omeprazole sulfone, and 5-hydroxy (5-OH) omeprazole were determined by liquid chromatography with tandem mass spectrometry (LC-MS/MS). The noncompartmental method was used for the determination of PK parameters. Change of mean pH and proportion (%) of time of gastric pH above 4.0 were estimated. The poor metabolizer (PM) group had the lowest metabolic ratio and exhibited the highest area under the curve (AUC) for omeprazole among the CYP2C19 phenotype groups. The PM group showed the greatest change of mean pH and the highest % time of gastric pH above 4.0. The relationship between AUC of omeprazole and % time of gastric pH above 4.0 was confirmed. The study demonstrates that CYP2C19*2 and *3 influence the PKs and PDs of omeprazole in Korean healthy volunteers. Clinical trial registry at the U.S. National Institutes of Health (https://clinicaltrials.gov), number NCT02299687.

No MeSH data available.


PK profiles of omeprazole and its metabolites in relation to CYP2C19 phenotypes. Plasma concentrations of omeprazole, 5-OH omeprazole, and omeprazole sulfone after single dosing (A, C, E), and multiple dosing (B, D, F).PK = pharmacokinetic, PM = poor metabolizer, IM = internal medicine, EM = emergency medicine.
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Figure 3: PK profiles of omeprazole and its metabolites in relation to CYP2C19 phenotypes. Plasma concentrations of omeprazole, 5-OH omeprazole, and omeprazole sulfone after single dosing (A, C, E), and multiple dosing (B, D, F).PK = pharmacokinetic, PM = poor metabolizer, IM = internal medicine, EM = emergency medicine.

Mentions: Time profiles of mean concentration and standard deviation in the concentration of omeprazole and its metabolites according to CYP2C19 phenotypes are shown in Fig. 3. Table 2 displays AUC0→12hr values of omeprazole, metabolic ratios 5-OH omeprazole (AUC0→12hr, 5-OH omeprazole/omeprazole) after single and multiple dosing, and the GMRs of the metabolic ratios. The AUC0→12hr of omeprazole (active form) in the PM group was higher than in the internal medicine (IM) and emergency medicine (EM) groups after single and multiple dosing. In all 3 groups, the AUC0→12hr of omeprazole increased after repeated administration. The metabolic ratio omeprazole sulfone (AUC0→12hr, 5-OH omeprazole/omeprazole) in the CYP2C19 PM group was lower than in the EM and IM groups after single dosing (GMR of metabolic ratios = 9.35 and 11.57, respectively). After repeated administration, this trend was maintained but to a lesser degree. With respect to metabolic transformation of omeprazole into omeprazole sulfone, no significant differences in the metabolic ratios were found among the 3 phenotypic groups after multiple dosing.


Effects of CYP2C19 Genetic Polymorphisms on PK/PD Responses of Omeprazole in Korean Healthy Volunteers
PK profiles of omeprazole and its metabolites in relation to CYP2C19 phenotypes. Plasma concentrations of omeprazole, 5-OH omeprazole, and omeprazole sulfone after single dosing (A, C, E), and multiple dosing (B, D, F).PK = pharmacokinetic, PM = poor metabolizer, IM = internal medicine, EM = emergency medicine.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5383603&req=5

Figure 3: PK profiles of omeprazole and its metabolites in relation to CYP2C19 phenotypes. Plasma concentrations of omeprazole, 5-OH omeprazole, and omeprazole sulfone after single dosing (A, C, E), and multiple dosing (B, D, F).PK = pharmacokinetic, PM = poor metabolizer, IM = internal medicine, EM = emergency medicine.
Mentions: Time profiles of mean concentration and standard deviation in the concentration of omeprazole and its metabolites according to CYP2C19 phenotypes are shown in Fig. 3. Table 2 displays AUC0→12hr values of omeprazole, metabolic ratios 5-OH omeprazole (AUC0→12hr, 5-OH omeprazole/omeprazole) after single and multiple dosing, and the GMRs of the metabolic ratios. The AUC0→12hr of omeprazole (active form) in the PM group was higher than in the internal medicine (IM) and emergency medicine (EM) groups after single and multiple dosing. In all 3 groups, the AUC0→12hr of omeprazole increased after repeated administration. The metabolic ratio omeprazole sulfone (AUC0→12hr, 5-OH omeprazole/omeprazole) in the CYP2C19 PM group was lower than in the EM and IM groups after single dosing (GMR of metabolic ratios = 9.35 and 11.57, respectively). After repeated administration, this trend was maintained but to a lesser degree. With respect to metabolic transformation of omeprazole into omeprazole sulfone, no significant differences in the metabolic ratios were found among the 3 phenotypic groups after multiple dosing.

View Article: PubMed Central - PubMed

ABSTRACT

The aim of this study was to examine the effects of CYP2C19*2 and *3 genetic polymorphisms on omeprazole pharmacokinetic (PK) and pharmacodynamic (PD) responses. Twenty-four healthy Korean volunteers were enrolled and given 20 mg omeprazole orally once daily for 8 days. The genotypes of CYP2C19 single nucleotide polymorphisms (SNPs) (*2, *3, and *17) were screened. The plasma concentrations of omeprazole, omeprazole sulfone, and 5-hydroxy (5-OH) omeprazole were determined by liquid chromatography with tandem mass spectrometry (LC-MS/MS). The noncompartmental method was used for the determination of PK parameters. Change of mean pH and proportion (%) of time of gastric pH above 4.0 were estimated. The poor metabolizer (PM) group had the lowest metabolic ratio and exhibited the highest area under the curve (AUC) for omeprazole among the CYP2C19 phenotype groups. The PM group showed the greatest change of mean pH and the highest % time of gastric pH above 4.0. The relationship between AUC of omeprazole and % time of gastric pH above 4.0 was confirmed. The study demonstrates that CYP2C19*2 and *3 influence the PKs and PDs of omeprazole in Korean healthy volunteers. Clinical trial registry at the U.S. National Institutes of Health (https://clinicaltrials.gov), number NCT02299687.

No MeSH data available.