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Research ArticleArticle

Association of Plasma Concentration of 4β-Hydroxycholesterol with CYP3A5 Polymorphism and Plasma Concentration of Indoxyl Sulfate in Stable Kidney Transplant Recipients

Yosuke Suzuki, Hiroki Itoh, Takashi Fujioka, Fuminori Sato, Kanako Kawasaki, Yukie Sato, Yuhki Sato, Keiko Ohno, Hiromitsu Mimata and Satoshi Kishino
Drug Metabolism and Disposition January 2014, 42 (1) 105-110; DOI: https://doi.org/10.1124/dmd.113.054171
Yosuke Suzuki
Department of Clinical Pharmacy, Oita University Hospital, Hasama-machi, Oita, Japan (Y.S., H.I., T.F., K.K., Y.S., Y.S.); Department of Urology, Faculty of Medicine, Oita University, Hasama-machi, Oita, Japan (F.S., H.M.); and Department of Medication Use Analysis and Clinical Research, Meiji Pharmaceutical University, Kiyose, Tokyo, Japan (K.O., S.K.).
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Hiroki Itoh
Department of Clinical Pharmacy, Oita University Hospital, Hasama-machi, Oita, Japan (Y.S., H.I., T.F., K.K., Y.S., Y.S.); Department of Urology, Faculty of Medicine, Oita University, Hasama-machi, Oita, Japan (F.S., H.M.); and Department of Medication Use Analysis and Clinical Research, Meiji Pharmaceutical University, Kiyose, Tokyo, Japan (K.O., S.K.).
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Takashi Fujioka
Department of Clinical Pharmacy, Oita University Hospital, Hasama-machi, Oita, Japan (Y.S., H.I., T.F., K.K., Y.S., Y.S.); Department of Urology, Faculty of Medicine, Oita University, Hasama-machi, Oita, Japan (F.S., H.M.); and Department of Medication Use Analysis and Clinical Research, Meiji Pharmaceutical University, Kiyose, Tokyo, Japan (K.O., S.K.).
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Fuminori Sato
Department of Clinical Pharmacy, Oita University Hospital, Hasama-machi, Oita, Japan (Y.S., H.I., T.F., K.K., Y.S., Y.S.); Department of Urology, Faculty of Medicine, Oita University, Hasama-machi, Oita, Japan (F.S., H.M.); and Department of Medication Use Analysis and Clinical Research, Meiji Pharmaceutical University, Kiyose, Tokyo, Japan (K.O., S.K.).
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Kanako Kawasaki
Department of Clinical Pharmacy, Oita University Hospital, Hasama-machi, Oita, Japan (Y.S., H.I., T.F., K.K., Y.S., Y.S.); Department of Urology, Faculty of Medicine, Oita University, Hasama-machi, Oita, Japan (F.S., H.M.); and Department of Medication Use Analysis and Clinical Research, Meiji Pharmaceutical University, Kiyose, Tokyo, Japan (K.O., S.K.).
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Yukie Sato
Department of Clinical Pharmacy, Oita University Hospital, Hasama-machi, Oita, Japan (Y.S., H.I., T.F., K.K., Y.S., Y.S.); Department of Urology, Faculty of Medicine, Oita University, Hasama-machi, Oita, Japan (F.S., H.M.); and Department of Medication Use Analysis and Clinical Research, Meiji Pharmaceutical University, Kiyose, Tokyo, Japan (K.O., S.K.).
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Yuhki Sato
Department of Clinical Pharmacy, Oita University Hospital, Hasama-machi, Oita, Japan (Y.S., H.I., T.F., K.K., Y.S., Y.S.); Department of Urology, Faculty of Medicine, Oita University, Hasama-machi, Oita, Japan (F.S., H.M.); and Department of Medication Use Analysis and Clinical Research, Meiji Pharmaceutical University, Kiyose, Tokyo, Japan (K.O., S.K.).
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Keiko Ohno
Department of Clinical Pharmacy, Oita University Hospital, Hasama-machi, Oita, Japan (Y.S., H.I., T.F., K.K., Y.S., Y.S.); Department of Urology, Faculty of Medicine, Oita University, Hasama-machi, Oita, Japan (F.S., H.M.); and Department of Medication Use Analysis and Clinical Research, Meiji Pharmaceutical University, Kiyose, Tokyo, Japan (K.O., S.K.).
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Hiromitsu Mimata
Department of Clinical Pharmacy, Oita University Hospital, Hasama-machi, Oita, Japan (Y.S., H.I., T.F., K.K., Y.S., Y.S.); Department of Urology, Faculty of Medicine, Oita University, Hasama-machi, Oita, Japan (F.S., H.M.); and Department of Medication Use Analysis and Clinical Research, Meiji Pharmaceutical University, Kiyose, Tokyo, Japan (K.O., S.K.).
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Satoshi Kishino
Department of Clinical Pharmacy, Oita University Hospital, Hasama-machi, Oita, Japan (Y.S., H.I., T.F., K.K., Y.S., Y.S.); Department of Urology, Faculty of Medicine, Oita University, Hasama-machi, Oita, Japan (F.S., H.M.); and Department of Medication Use Analysis and Clinical Research, Meiji Pharmaceutical University, Kiyose, Tokyo, Japan (K.O., S.K.).
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Abstract

Several studies have shown that renal failure decreases CYP3A activity and that uremic toxins may play a role via transcriptional or translational modifications of cytochrome P450 (P450) enzymes and direct inhibition of P450-mediated metabolism. In this study, we evaluated the relationship between CYP3A activity (using plasma concentration of 4β-hydroxycholesterol as a biomarker) and clinical characteristics including plasma concentrations of indoxyl sulfate (3-INDS) and indole-3-acetic acid (3-IAA) in stable kidney transplant recipients. Forty-five Japanese kidney transplant recipients who underwent transplantation more than 90 days prior to the study were included. Morning blood samples were collected and plasma concentrations of 4β-hydroxycholesterol, 3-INDS, and 3-IAA were measured. Plasma concentrations of 4β-hydroxycholesterol were 57.1 ± 11.2, 42.1 ± 11.8, and 34.5 ± 7.3 ng/ml in recipients with CYP3A5*1/*1 (n = 5), *1/*3 (n = 15), and *3/*3 (n = 25) genotypes, respectively, with significant differences between three genotypes. A significant correlation was observed between plasma concentrations of 4β-hydroxycholesterol and 3-INDS but not 3-IAA. Multiple regression analysis identified the number of CYP3A5*3 alleles in genotype, plasma concentration of 3-INDS, and body weight as independent variables associated with plasma concentration of 4β-hydroxycholesterol. In conclusion, these results suggest that CYP3A5 polymorphism and plasma concentration of 3-INDS may account for the interindividual variability of CYP3A activity, and that plasma concentration of 3-INDS may partially explain the gap in CYP3A activity that cannot be explained by genetic contribution in patients with renal failure.

Footnotes

    • Received August 12, 2013.
    • Accepted October 17, 2013.
  • dx.doi.org/10.1124/dmd.113.054171.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 42 (1)
Drug Metabolism and Disposition
Vol. 42, Issue 1
1 Jan 2014
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Research ArticleArticle

4β-OHC Depends on CYP3A5 Polymorphism and 3-INDS

Yosuke Suzuki, Hiroki Itoh, Takashi Fujioka, Fuminori Sato, Kanako Kawasaki, Yukie Sato, Yuhki Sato, Keiko Ohno, Hiromitsu Mimata and Satoshi Kishino
Drug Metabolism and Disposition January 1, 2014, 42 (1) 105-110; DOI: https://doi.org/10.1124/dmd.113.054171

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Research ArticleArticle

4β-OHC Depends on CYP3A5 Polymorphism and 3-INDS

Yosuke Suzuki, Hiroki Itoh, Takashi Fujioka, Fuminori Sato, Kanako Kawasaki, Yukie Sato, Yuhki Sato, Keiko Ohno, Hiromitsu Mimata and Satoshi Kishino
Drug Metabolism and Disposition January 1, 2014, 42 (1) 105-110; DOI: https://doi.org/10.1124/dmd.113.054171
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