title: Isolation and identification of intestinal CYP3A inhibitors from cranberry (Vaccinium macrocarpon) using human intestinal microsomes.
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: Herbal Medicinal Products Division, Korea Food and Drug Administration, Seoul, Republic of Korea.
authors: Eunkyung
authors: E
authors: Kim
authors: Arlene
authors: A
authors: Sy-Cordero
authors: Tyler N
authors: TN
authors: Graf
authors: Scott J
authors: SJ
authors: Brantley
authors: Mary F
authors: MF
authors: Paine
authors: Nicholas H
authors: NH
authors: Oberlies
mesh_terms: D001628:Beverages; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018565:Food-Drug Interactions; D005638:Fruit; D006801:Humans; D007422:Intestines / Q000187:drug effects* / Q000201:enzymology; D008861:Microsomes / Q000187:drug effects; D008874:Midazolam / Q000378:metabolism*; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology*; D011994:Recombinant Proteins; D014315:Triterpenes / Q000302:isolation & purification / Q000494:pharmacology*; D029799:Vaccinium macrocarpon / Q000737:chemistry*
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D010936:Plant Extracts; D011994:Recombinant Proteins; D014315:Triterpenes; D008874:Midazolam