Classical inhibitors of human cytochrome P450 3A4 activity, such as ketoconazol and quercetin, are tested to prove the efficiency of a new metabolisation model using living entire cells. Grapefruit juice is a well-known potent inhibitor of cytochrome P450 3A4 activity. With regard to the clinical relevance of grapefruit juice-drug interactions, an investigation of other common juices is undertaken with this in vitro model. The CYP3A4 activity is measured by the formation of the 6beta-hydroxytestosterone, which is quantified by an isocratic high performance liquid chromatography. It is demonstrated for the first time that lemon juice significantly inhibits by 60+/-3% the CYP3A4-mediated oxidation. Grapefruit juice inhibits this activity by 82+/-4%. The mechanism of lemon juice inhibition is competitive, whereas it is mixed for grapefruit juice. These results suggest that our in vitro model combined with our analytical method is applicable for the investigation of the inhibition of CYP3A4 not only by chemical inhibitors but also by natural food products.

Grapefruit juice has been found to interact with many oral drugs when taken concomitantly. Studies have shown that grapefruit juice inhibits cytochrome P450 3A4 (CYP3A4)- an important enzyme involved in drug metabolism- via mechanism-based inactivation. Drug elimination is therefore prevented, and as a result, the bioavailability of many orally administered drugs is substantially increased when the patient ingests grapefruit juice. The grapefruit-drug interaction may result in severe side effects, ranging from hypotension to fatal cardiac arrhythmias. The active ingredients in grapefruit juice are substances of the coumarin family, primarily 6'7'-dihydroxybergamottin (DHB), a compound that inhibits CYP3A4 by causing irreversible inactivation of the enzyme. A flavenoid, naringenin, is also though to play a minor role. Furthermore, the effects of grapefruit juice can last over 24 hours since last consumption. Because many drugs, including felodipine, terfenadine, cyclosporine, and saquinavir, are metabolized by CYP3A4, it is very important to be aware of the potential side effects if grapefruit juice is consumed while patients are on medications that are metabolized by this enzyme.

Grapefruit juice can inhibit the gastrointestinal activity of cytochrome P450 (CYP) 3A4, while its effect on CYP1A2 remains controversial. Several grapefruit juice bioflavonoids also modulate the activity of the drug transporter P-glycoprotein in the gut and in the blood-brain barrier. Both CYP1A2 and CYP3A4 are involved in clozapine metabolism. This study investigated the effects of repeated ingestion of grapefruit juice on multiple-dose pharmacokinetics and pharmacodynamics of clozapine in schizophrenic patients.Clozapine therapy was initiated for fifteen treatment-resistant schizophrenic inpatients (DSM-IV criteria). The doses were individually titrated from day -35 to day -15 and then kept unchanged from day -14 to day 49. Regular-strength grapefruit juice (250 mL) was coadministered b.i.d. with each clozapine dose from day 15 to day 28. Plasma levels of clozapine and its main metabolites (norclozapine and clozapine N-oxide) were obtained, and clinical efficacy and safety assessments were completed prior to juice administration (days 0, 7, and 14), during the coadministration (days 17, 21, and 28), and after cessation of the juice (days 35, 42, and 49).After reaching steady states, plasma concentrations of clozapine and its metabolites and Positive and Negative Syndrome Scale scores were not significantly altered by the effect of grapefruit juice ingestion. The Clinical Global Impressions scale scores, Calgary Depression Scale scores, and side effect profiles (by the Extr

1. The presence of inhibitors of drug efflux transporters, such as P-glycoprotein (P-gp), in grapefruit juice (GFJ) was confirmed based on the uptake of [(3)H]-vinblastine (VBL) by Caco-2 cells. 2. The uptake of [(3)H]-VBL by Caco-2 cells was significantly increased by the ethyl acetate extract of GFJ as well as by cyclosporin A. The extract was separated on a Cosmosil column and the eluate with 60% methanol increased [(3)H]-VBL uptake, while the activity to inhibit CYP3A4 was greatest in the 70 and 80% eluates. 3. These results show that the major inhibitor of efflux transport of VBL is diffe

ABSTRACT: The cytochrome P450 enzyme family is the most abundant and responsible for the metabolism of more than 60% of currently marketed drugs and is considered central in many clinically important drug interactions. Seven different grapefruit and pummelo juices as well as 5 furocoumarins isolated from grapefruit juice were evaluated at different concentration on cytochrome P450 3A4 (CYP3A4), cytochrome P450 2C9 (CYP2C9), and cytochrome P450 2D6 (CYP2D6) isoenzyme activity. Grapefruit and pummelo juices were found to be potent inhibitors of cytochrome CYP3A4 and CYP2C9 isoenzymes at 25% conc

Grapefruit juice has been shown to increase the oral bioavailability of several clinically important drugs by inhibiting first pass metabolism. Several compounds in grapefruit juice have shown different biological activities. Unique among them are furocoumarins with potent inhibitory activity against cytochrome P450 enzymes. In the present study, two bioactive compounds were isolated from grapefruit juice and grapefruit peel oil. The purity of the isolated compounds has been analyzed by HPLC. Structures of the compounds were elucidated by extensive NMR and mass spectral studies and identified

Plant-drug interactions mediated by cytochrome P450 (CYP450) enzymes are a critical area of study owing to their potential to alter drug metabolism, efficacy, and toxicity. This review examines how common phytochemicals such as flavonoids, polyphenols, alkaloids, and terpenes modulate CYP450 activity and influence drug pharmacokinetics. Key clinical implications include changes in drug effectiveness, increased adverse effects, and therapeutic failure, as illustrated by interactions such as St. John’s Wort with CYP3A4 substrates, grapefruit juice inhibiting CYP3A4, and garlic affecting anticoag

PURPOSE: Grapefruit juice (GJ) is known to increase the oral bioavailability of many CYP3A-substrates by inhibiting intestinal phase-I metabolism. However, the magnitude of AUC increase is often insignificant and highly variable. Since we earlier suggested that CYP3A and P-glycoprotein (P-gp) form a concerted barrier to drug absorption, we investigated the role of P-gp in GJ-drug interactions. METHODS: The transcellular bidirectional flux of drugs that are (i) CYP3A-and/or P-gp substrates (Vinblastine, Cyclosporine, Digoxin, Fexofenadine, Losartan) or that are (ii) primary CYP3A-substrates (Fe

Some chemical components involved in grapefruit juice and St. John's wort can produce changes in pharmacological activity of different drugs; however, their interaction with both P-glycoprotein and CyP450 enzyme is not clear. The aim of this study was to evaluate the possible interaction of epoxybergamoti, hyperforin and hypericin with both P-glycoprotein and CyP450 enzyme using 1w0f, 3g5u proteins, midazolam, simvastatin and fexofenadine as theoretical tools in DockingServer program. The results showed differences in the aminoacid residues involved in the interaction of epoxybergamoti, hyperf