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Hydroxylation of R(+)- and S(−)-Omeprazole after Racemic Dosing are Different among the CYP2C19 Genotypes

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ABSTRACT

Purpose

To elucidate the stereoselective pharmacokinetics of omeprazole enantiomers and their metabolites after racemic IV dosing because there is little information about the stereoselective metabolism of omeprazole in in vivo study.

Methods

Seventeen subjects were classified into three CYP2C19 groups based on their genotypes: homozygous extensive metabolizers (hmEMs; n = 5), heterozygous EMs (htEMs; n = 7) and poor metabolizers (PMs; n = 5).

Results

After single IV administration of racemic omeprazole (20 mg), the mean area under the plasma concentration-time curve (AUC0-∞) of R(+)-omeprazole in PMs was significantly higher than that in hmEMs and htEMs, while that of S(−)-omeprazole was no significance among three genotypes because of a wide inter-individual variability. In addition, although the AUC0-∞ of R(+)-5-hydroxyomeprazole were determined among three genotypes, the that of S(−)-5-hydroxyomeprazole was undetectable in the hmEMs and barely detectable in the htEMs. Conversly, the AUC0-∞ of S(−)-5-hydroxyomeprazole was greater than that of R(+)-5-hydroxyomeprazole in the PMs.

Conclusions

These data therefore suggest that, for EMs, the CYP2C19-mediated formation from R(+)-enantiomer is a 5-hydroxy-metabolite, while that from S(−)-enantiomer may be a minor metabolite. Thus, the in vivo disposition of S(−)- and R(+)-omeprazole after racemic dosing may be different among the CYP2C19 genotypes.

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Abbreviations

AUC:

area under the plasma concentration-time curve

Cmax :

maximum plasma concentration

CYP:

cytochrome P450

hmEMs:

homozygous extensive metabolizers

HPLC:

high-performance liquid chromatography

htEMs:

heterozygous extensive metabolizers

IV:

intravenous

ke:

elimination rate constant

PMs:

poor metabolizers

PO:

oral administration

PPI:

proton pump inhibitor

t1/2 :

elimination half-life

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ACKNOWLEDGMENTS & DISCLOSURES

This works was supported by Grants-in-Aid for Scientific Research (no. 20590150) Tokyo, Japan.

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Authors and Affiliations

  1. Department of Hospital Pharmacy, Faculty of Medicine University of the Ryukyus, 207 Uehara, Nishihara-cho, Okinawa, 903-0215, Japan

    Hideo Shiohira, Satoshi Yamada, Yumiko Akamine & Tsukasa Uno

  2. Department of Neuropsychiatry, Hirosaki University School of Medicine, Hirosaki, Japan

    Norio Yasui-Furukori

  3. Pharmaceuticals and Medical Devices Agency, Tokyo, Japan

    Tomonori Tateishi

Authors
  1. Hideo Shiohira
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  2. Norio Yasui-Furukori
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  3. Satoshi Yamada
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  4. Tomonori Tateishi
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  5. Yumiko Akamine
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  6. Tsukasa Uno
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Corresponding author

Correspondence to Tsukasa Uno.

Additional information

Hideo Shiohira, Norio Yasui-Furukori, and Satoshi Yamada contributed equally to this manuscript.

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Shiohira, H., Yasui-Furukori, N., Yamada, S. et al. Hydroxylation of R(+)- and S(−)-Omeprazole after Racemic Dosing are Different among the CYP2C19 Genotypes. Pharm Res 29, 2310–2316 (2012). https://doi.org/10.1007/s11095-012-0757-x

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  • DOI: https://doi.org/10.1007/s11095-012-0757-x

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