Pharmacogenomic/pharmacokinetic assessment of a four-probe cocktail for CYPs and OATPs following oral microdosing

Ichiro Ieiri, Masato Fukae, Kazuya Maeda, Yukie Ando, Miyuki Kimura, Takeshi Hirota, Takeshi Nakamura, Kazuhide Iwasaki, Shunji Matsuki, Kyoko Matsuguma, Eri Kanda, Mariko Deguchi, Shin Irie, Yuichi Sugiyama

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Abstract

Objectives: To test whether the multiple phenotype and genotype relationships established using therapeutic dose, can be reproduced following oral microdosing using substrates of CYP2C9 (warfarin and glibenclamide), CYP2C19 (lansoprazole), CYP2D6 (dextromethorphan), and OATPs (glibenclamide). Methods: A cocktail of test drugs was administered orally under the microdose in liquid or capsule form, and then a therapeutic dose of dextromethorphan was administered to 17 healthy subjects whose genotypes for CYPs and OATPs had been prescreened. Concentrations of the drugs and their metabolites were measured by LC-MS/MS. Results: The AUC and t 1/2 of glibenclamide following the microdosing tended to be higher and longer, respectively, in CYP2C9*1/*3 than CYP2C9*1/*1 subjects. In contrast, there were no significant differences in any of the pharmacokinetic parameters for warfarin between the two genotypes. For CYP2D6 following the therapeutic dose, there was good concordance between genotype and phenotype; however, such relationships disappeared after microdosing. For CYP2C19 following the microdosing, there were significant differences between EMs and PMs in the pharmacokinetic parameters of lansoprazole. The relative AUC 0-12 ratio of lansoprazole in EMs and PMs was 1:3.3-4.3. Among test drugs, phenotypic measurements of lansoprazole accorded well with the CYP2C19 genotype at the microdose as well as therapeutic dose. Conclusions: The present study suggests that 1) the sampling strategy should be optimized according to pharmacokinetic profiles of the test drugs following oral microdosing, and 2) microdosing can be applied to the pharmacogenomic study of CYP-specific drugs.

Original languageEnglish
Pages (from-to)689-700
Number of pages12
JournalInternational Journal of Clinical Pharmacology and Therapeutics
Volume50
Issue number10
DOIs
Publication statusPublished - Oct 1 2012

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Pharmacogenetics
Lansoprazole
Pharmacokinetics
Genotype
Glyburide
Dextromethorphan
Cytochrome P-450 CYP2D6
Pharmaceutical Preparations
Warfarin
Area Under Curve
Phenotype
Therapeutics
Capsules
Healthy Volunteers
Cytochrome P-450 CYP2C9
Cytochrome P-450 CYP2C19

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)

Cite this

Pharmacogenomic/pharmacokinetic assessment of a four-probe cocktail for CYPs and OATPs following oral microdosing. / Ieiri, Ichiro; Fukae, Masato; Maeda, Kazuya; Ando, Yukie; Kimura, Miyuki; Hirota, Takeshi; Nakamura, Takeshi; Iwasaki, Kazuhide; Matsuki, Shunji; Matsuguma, Kyoko; Kanda, Eri; Deguchi, Mariko; Irie, Shin; Sugiyama, Yuichi.

In: International Journal of Clinical Pharmacology and Therapeutics, Vol. 50, No. 10, 01.10.2012, p. 689-700.

Research output: Contribution to journalArticle

Ieiri, I, Fukae, M, Maeda, K, Ando, Y, Kimura, M, Hirota, T, Nakamura, T, Iwasaki, K, Matsuki, S, Matsuguma, K, Kanda, E, Deguchi, M, Irie, S & Sugiyama, Y 2012, 'Pharmacogenomic/pharmacokinetic assessment of a four-probe cocktail for CYPs and OATPs following oral microdosing', International Journal of Clinical Pharmacology and Therapeutics, vol. 50, no. 10, pp. 689-700. https://doi.org/10.5414/CP201763
Ieiri, Ichiro ; Fukae, Masato ; Maeda, Kazuya ; Ando, Yukie ; Kimura, Miyuki ; Hirota, Takeshi ; Nakamura, Takeshi ; Iwasaki, Kazuhide ; Matsuki, Shunji ; Matsuguma, Kyoko ; Kanda, Eri ; Deguchi, Mariko ; Irie, Shin ; Sugiyama, Yuichi. / Pharmacogenomic/pharmacokinetic assessment of a four-probe cocktail for CYPs and OATPs following oral microdosing. In: International Journal of Clinical Pharmacology and Therapeutics. 2012 ; Vol. 50, No. 10. pp. 689-700.
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T1 - Pharmacogenomic/pharmacokinetic assessment of a four-probe cocktail for CYPs and OATPs following oral microdosing

AU - Ieiri, Ichiro

AU - Fukae, Masato

AU - Maeda, Kazuya

AU - Ando, Yukie

AU - Kimura, Miyuki

AU - Hirota, Takeshi

AU - Nakamura, Takeshi

AU - Iwasaki, Kazuhide

AU - Matsuki, Shunji

AU - Matsuguma, Kyoko

AU - Kanda, Eri

AU - Deguchi, Mariko

AU - Irie, Shin

AU - Sugiyama, Yuichi

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Y1 - 2012/10/1

N2 - Objectives: To test whether the multiple phenotype and genotype relationships established using therapeutic dose, can be reproduced following oral microdosing using substrates of CYP2C9 (warfarin and glibenclamide), CYP2C19 (lansoprazole), CYP2D6 (dextromethorphan), and OATPs (glibenclamide). Methods: A cocktail of test drugs was administered orally under the microdose in liquid or capsule form, and then a therapeutic dose of dextromethorphan was administered to 17 healthy subjects whose genotypes for CYPs and OATPs had been prescreened. Concentrations of the drugs and their metabolites were measured by LC-MS/MS. Results: The AUC and t 1/2 of glibenclamide following the microdosing tended to be higher and longer, respectively, in CYP2C9*1/*3 than CYP2C9*1/*1 subjects. In contrast, there were no significant differences in any of the pharmacokinetic parameters for warfarin between the two genotypes. For CYP2D6 following the therapeutic dose, there was good concordance between genotype and phenotype; however, such relationships disappeared after microdosing. For CYP2C19 following the microdosing, there were significant differences between EMs and PMs in the pharmacokinetic parameters of lansoprazole. The relative AUC 0-12 ratio of lansoprazole in EMs and PMs was 1:3.3-4.3. Among test drugs, phenotypic measurements of lansoprazole accorded well with the CYP2C19 genotype at the microdose as well as therapeutic dose. Conclusions: The present study suggests that 1) the sampling strategy should be optimized according to pharmacokinetic profiles of the test drugs following oral microdosing, and 2) microdosing can be applied to the pharmacogenomic study of CYP-specific drugs.

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