Processing grapefruit juice with γ-cyclodextrin attenuates its inhibitory effect on cytochrome P450 3A activity

Keishi Yamasaki, Daisuke Iohara, Yoko Oyama, Narumi Nishizaki, Seitaro Kawazu, Koji Nishi, Daisuke Kadowaki, Kazuaki Taguchi, Masaki Otagiri, Hakaru Seo

Research output: Contribution to journalArticle

Abstract

Objectives: Grapefruit (Citrus paradisi) juice enhances the oral bioavailability of drugs that are metabolized by intestinal cytochrome P450 3A4 (CYP3A4). Patients are advised to avoid drinking grapefruit juice to prevent this drug–grapefruit juice interaction. The aim of this study was to investigate whether processing grapefruit juice with cyclodextrins (CDs) would result in preventing or inhibiting this interaction. Methods: Grapefruit juice and the major furanocoumarins found in grapefruit, bergamottin (BG) and 6′, 7′-dihydroxy bergamottin (DHBG) were mixed with α, β and γCDs. The effects of these processed juice samples and furanocoumarins on CYP3A activity were compared with the corresponding values for unprocessed juices and furanocoumarins. Interactions between CDs and these furanocoumarins were also investigated by phase solubility and 1H NMR studies. Key findings: The inhibition of CYP3A by grapefruit juice was significantly attenuated by processing particularly with γCD. Similar attenuation effects by γCD were observed in the cases of BG and DHBG. Furthermore, BG and DHBG were suggested to be strongly encapsulated in the cavity of γCD. Conclusion: The encapsulation of BG and DHBG by γCD and the resulting attenuation of the inhibition of CYP3A activity by grapefruit juice may be applicable to juice processing for preventing drug-grapefruit juice interactions.

Original languageEnglish
JournalJournal of Pharmacy and Pharmacology
DOIs
Publication statusAccepted/In press - 2019 Jan 1

Fingerprint

Citrus paradisi
Cytochrome P-450 CYP3A
Cyclodextrins
bergamottin
Pharmaceutical Preparations
Solubility
Biological Availability
Drinking

Keywords

  • cyclodextrins
  • cytochrome P450
  • drug interaction
  • grapefruit juice

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

Cite this

Processing grapefruit juice with γ-cyclodextrin attenuates its inhibitory effect on cytochrome P450 3A activity. / Yamasaki, Keishi; Iohara, Daisuke; Oyama, Yoko; Nishizaki, Narumi; Kawazu, Seitaro; Nishi, Koji; Kadowaki, Daisuke; Taguchi, Kazuaki; Otagiri, Masaki; Seo, Hakaru.

In: Journal of Pharmacy and Pharmacology, 01.01.2019.

Research output: Contribution to journalArticle

Yamasaki, Keishi ; Iohara, Daisuke ; Oyama, Yoko ; Nishizaki, Narumi ; Kawazu, Seitaro ; Nishi, Koji ; Kadowaki, Daisuke ; Taguchi, Kazuaki ; Otagiri, Masaki ; Seo, Hakaru. / Processing grapefruit juice with γ-cyclodextrin attenuates its inhibitory effect on cytochrome P450 3A activity. In: Journal of Pharmacy and Pharmacology. 2019.
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AU - Iohara, Daisuke

AU - Oyama, Yoko

AU - Nishizaki, Narumi

AU - Kawazu, Seitaro

AU - Nishi, Koji

AU - Kadowaki, Daisuke

AU - Taguchi, Kazuaki

AU - Otagiri, Masaki

AU - Seo, Hakaru

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N2 - Objectives: Grapefruit (Citrus paradisi) juice enhances the oral bioavailability of drugs that are metabolized by intestinal cytochrome P450 3A4 (CYP3A4). Patients are advised to avoid drinking grapefruit juice to prevent this drug–grapefruit juice interaction. The aim of this study was to investigate whether processing grapefruit juice with cyclodextrins (CDs) would result in preventing or inhibiting this interaction. Methods: Grapefruit juice and the major furanocoumarins found in grapefruit, bergamottin (BG) and 6′, 7′-dihydroxy bergamottin (DHBG) were mixed with α, β and γCDs. The effects of these processed juice samples and furanocoumarins on CYP3A activity were compared with the corresponding values for unprocessed juices and furanocoumarins. Interactions between CDs and these furanocoumarins were also investigated by phase solubility and 1H NMR studies. Key findings: The inhibition of CYP3A by grapefruit juice was significantly attenuated by processing particularly with γCD. Similar attenuation effects by γCD were observed in the cases of BG and DHBG. Furthermore, BG and DHBG were suggested to be strongly encapsulated in the cavity of γCD. Conclusion: The encapsulation of BG and DHBG by γCD and the resulting attenuation of the inhibition of CYP3A activity by grapefruit juice may be applicable to juice processing for preventing drug-grapefruit juice interactions.

AB - Objectives: Grapefruit (Citrus paradisi) juice enhances the oral bioavailability of drugs that are metabolized by intestinal cytochrome P450 3A4 (CYP3A4). Patients are advised to avoid drinking grapefruit juice to prevent this drug–grapefruit juice interaction. The aim of this study was to investigate whether processing grapefruit juice with cyclodextrins (CDs) would result in preventing or inhibiting this interaction. Methods: Grapefruit juice and the major furanocoumarins found in grapefruit, bergamottin (BG) and 6′, 7′-dihydroxy bergamottin (DHBG) were mixed with α, β and γCDs. The effects of these processed juice samples and furanocoumarins on CYP3A activity were compared with the corresponding values for unprocessed juices and furanocoumarins. Interactions between CDs and these furanocoumarins were also investigated by phase solubility and 1H NMR studies. Key findings: The inhibition of CYP3A by grapefruit juice was significantly attenuated by processing particularly with γCD. Similar attenuation effects by γCD were observed in the cases of BG and DHBG. Furthermore, BG and DHBG were suggested to be strongly encapsulated in the cavity of γCD. Conclusion: The encapsulation of BG and DHBG by γCD and the resulting attenuation of the inhibition of CYP3A activity by grapefruit juice may be applicable to juice processing for preventing drug-grapefruit juice interactions.

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