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Isolation and identification of intestinal CYP3A inhibitors from cranberry (Vaccinium macrocarpon) using human intestinal microsomes.
Planta Med. 2011 Feb; 77(3):265-70.PM

Abstract

Cranberry juice is used routinely, especially among women and the elderly, to prevent and treat urinary tract infections. These individuals are likely to be taking medications concomitantly with cranberry juice, leading to concern about potential drug-dietary substance interactions, particularly in the intestine, which, along with the liver, is rich in expression of the prominent drug metabolizing enzyme, cytochrome P450 3A (CYP3A). Using a systematic in vitro-in vivo approach, a cranberry juice product was identified recently that elicited a pharmacokinetic interaction with the CYP3A probe substrate midazolam in 16 healthy volunteers. Relative to water, cranberry juice inhibited intestinal first-pass midazolam metabolism. In vitro studies were initiated to identify potential enteric CYP3A inhibitors from cranberry via a bioactivity-directed fractionation approach involving dried whole cranberry [Vaccinium macrocarpon Ait. (Ericaceae)], midazolam, and human intestinal microsomes (HIM). Three triterpenes (maslinic acid, corosolic acid, and ursolic acid) were isolated. The inhibitory potency (IC(50)) of maslinic acid, corosolic acid, and ursolic acid was 7.4, 8.8, and < 10 µM, respectively, using HIM as the enzyme source and 2.8, 4.3, and < 10 µM, respectively, using recombinant CYP3A4 as the enzyme source. These in vitro inhibitory potencies, which are within the range of those reported for two CYP3A inhibitory components in grapefruit juice, suggest that these triterpenes may have contributed to the midazolam-cranberry juice interaction observed in the clinical study.

Authors+Show Affiliations

Herbal Medicinal Products Division, Korea Food and Drug Administration, Seoul, Republic of Korea.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Clinical Trial
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20717876

Citation

Kim, Eunkyung, et al. "Isolation and Identification of Intestinal CYP3A Inhibitors From Cranberry (Vaccinium Macrocarpon) Using Human Intestinal Microsomes." Planta Medica, vol. 77, no. 3, 2011, pp. 265-70.
Kim E, Sy-Cordero A, Graf TN, et al. Isolation and identification of intestinal CYP3A inhibitors from cranberry (Vaccinium macrocarpon) using human intestinal microsomes. Planta Med. 2011;77(3):265-70.
Kim, E., Sy-Cordero, A., Graf, T. N., Brantley, S. J., Paine, M. F., & Oberlies, N. H. (2011). Isolation and identification of intestinal CYP3A inhibitors from cranberry (Vaccinium macrocarpon) using human intestinal microsomes. Planta Medica, 77(3), 265-70. https://doi.org/10.1055/s-0030-1250259
Kim E, et al. Isolation and Identification of Intestinal CYP3A Inhibitors From Cranberry (Vaccinium Macrocarpon) Using Human Intestinal Microsomes. Planta Med. 2011;77(3):265-70. PubMed PMID: 20717876.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Isolation and identification of intestinal CYP3A inhibitors from cranberry (Vaccinium macrocarpon) using human intestinal microsomes. AU - Kim,Eunkyung, AU - Sy-Cordero,Arlene, AU - Graf,Tyler N, AU - Brantley,Scott J, AU - Paine,Mary F, AU - Oberlies,Nicholas H, Y1 - 2010/08/17/ PY - 2010/8/19/entrez PY - 2010/8/19/pubmed PY - 2011/9/29/medline SP - 265 EP - 70 JF - Planta medica JO - Planta Med. VL - 77 IS - 3 N2 - Cranberry juice is used routinely, especially among women and the elderly, to prevent and treat urinary tract infections. These individuals are likely to be taking medications concomitantly with cranberry juice, leading to concern about potential drug-dietary substance interactions, particularly in the intestine, which, along with the liver, is rich in expression of the prominent drug metabolizing enzyme, cytochrome P450 3A (CYP3A). Using a systematic in vitro-in vivo approach, a cranberry juice product was identified recently that elicited a pharmacokinetic interaction with the CYP3A probe substrate midazolam in 16 healthy volunteers. Relative to water, cranberry juice inhibited intestinal first-pass midazolam metabolism. In vitro studies were initiated to identify potential enteric CYP3A inhibitors from cranberry via a bioactivity-directed fractionation approach involving dried whole cranberry [Vaccinium macrocarpon Ait. (Ericaceae)], midazolam, and human intestinal microsomes (HIM). Three triterpenes (maslinic acid, corosolic acid, and ursolic acid) were isolated. The inhibitory potency (IC(50)) of maslinic acid, corosolic acid, and ursolic acid was 7.4, 8.8, and < 10 µM, respectively, using HIM as the enzyme source and 2.8, 4.3, and < 10 µM, respectively, using recombinant CYP3A4 as the enzyme source. These in vitro inhibitory potencies, which are within the range of those reported for two CYP3A inhibitory components in grapefruit juice, suggest that these triterpenes may have contributed to the midazolam-cranberry juice interaction observed in the clinical study. SN - 1439-0221 UR - https://www.unboundmedicine.com/medline/citation/20717876/Isolation_and_identification_of_intestinal_CYP3A_inhibitors_from_cranberry__Vaccinium_macrocarpon__using_human_intestinal_microsomes_ L2 - http://www.thieme-connect.com/DOI/DOI?10.1055/s-0030-1250259 DB - PRIME DP - Unbound Medicine ER -