| Grapefruit juice increases felodipine oral availability in humans by decreasing intestinal CYP3A protein expression. | |
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MedLine Citation:
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PMID: 9153299 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The increase in oral availability of felodipine and other commonly used medications when taken with grapefruit juice has been assumed to be due to inhibition of CYP3A4, a cytochrome P450 that is present in liver and intestine. To evaluate the effect of repeated grapefruit juice ingestion on CYP3A4 expression, 10 healthy men were given 8 oz of grapefruit juice three times a day for 6 d. Before and after receiving grapefruit juice, small bowel and colon mucosal biopsies were obtained endoscopically, oral felodipine kinetics were determined, and liver CYP3A4 activity was measured with the [14C N-methyl] erythromycin breath test in each subject. Grapefruit juice did not alter liver CYP3A4 activity, colon levels of CYP3A5, or small bowel concentrations of P-glycoprotein, villin, CYP1A1, and CYP2D6. In contrast, the concentration of CYP3A4 in small bowel epithelia (enterocytes) fell 62% (P = 0.0006) with no corresponding change in CYP3A4 mRNA levels. In addition, enterocyte concentrations of CYP3A4 measured before grapefruit juice consumption correlated with the increase in Cmax when felodipine was taken with either the 1st or the 16th glass of grapefruit juice relative to water (r = 0. 67, P = 0.043, and r = 0.71, P = 0.022, respectively). We conclude that a mechanism for the effect of grapefruit juice on oral felodipine kinetics is its selective downregulation of CYP3A4 in the small intestine. |
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Authors:
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K S Lown; D G Bailey; R J Fontana; S K Janardan; C H Adair; L A Fortlage; M B Brown; W Guo; P B Watkins |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: The Journal of clinical investigation Volume: 99 ISSN: 0021-9738 ISO Abbreviation: J. Clin. Invest. Publication Date: 1997 May |
Date Detail:
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Created Date: 1997-06-17 Completed Date: 1997-06-17 Revised Date: 2009-11-18 |
Medline Journal Info:
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Nlm Unique ID: 7802877 Medline TA: J Clin Invest Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 2545-53 Citation Subset: AIM; IM |
Affiliation:
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Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Administration, Oral Adult Aryl Hydrocarbon Hydroxylases* Beverages* Biopsy Citrus* Colon / cytology Cytochrome P-450 CYP3A Cytochrome P-450 Enzyme System / antagonists & inhibitors, biosynthesis*, metabolism Felodipine / administration & dosage, pharmacokinetics* Gene Expression Humans Intestinal Mucosa / cytology, enzymology* Intestine, Small / cytology Kinetics Liver / enzymology Male Mixed Function Oxygenases / antagonists & inhibitors, biosynthesis* Oxidoreductases, N-Demethylating / metabolism P-Glycoprotein / metabolism Reference Values |
| Grant Support | |
ID/Acronym/Agency:
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GM38149-11/GM/NIGMS NIH HHS; GM53095-01/GM/NIGMS NIH HHS; MO1 RR00042/RR/NCRR NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/P-Glycoprotein; 72509-76-3/Felodipine; 9035-51-2/Cytochrome P-450 Enzyme System; EC 1.-/Mixed Function Oxygenases; EC 1.14.13.67/CYP3A4 protein, human; EC 1.14.14.1/Aryl Hydrocarbon Hydroxylases; EC 1.14.14.1/CYP3A protein, human; EC 1.14.14.1/CYP3A5 protein, human; EC 1.14.14.1/Cytochrome P-450 CYP3A; EC 1.5.-/Oxidoreductases, N-Demethylating |
| Comments/Corrections | |
Comment In:
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J Clin Invest. 1997 May 15;99(10):2297-8
[PMID:
9153265
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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