Influence of grapefruit juice on itraconazole plasma levels in mice and guinea pigs. (1/89)

Levels of itraconazole and its metabolite hydroxy-itraconazole were measured by HPLC in plasma samples from guinea pigs and DBA/2 and BALB/c mice after oral or intraperitoneal treatment with itraconazole/cyclodextrin solution at 5 and 20 mg/kg daily for 7 days. The animals were randomly assigned to receive grapefruit juice or drinking water in their fluid bottles, since components of grapefruit juice have been found to alter the pharmacokinetic behaviour of pharmaceuticals that interact with cytochrome P450 enzymes. The results demonstrated clear differences in itraconazole pharmacokinetics between the three animal types studied. The total levels of antifungally active azole were highest in DBA/2 mice and lowest in guinea pigs, regardless of the route of administration. Guinea pigs that drank grapefruit juice had higher plasma levels of azoles after oral administration of the drug, but the juice did not influence levels of itraconazole or its metabolite in guinea pigs treated intraperitoneally, or in either mouse strain treated orally or intraperitoneally. This result indicates that grapefruit juice effects on the pharmacokinetics of itraconazole are species dependent and confined to the gastrointestinal tract, influencing drug absorption. Differences in itraconazole pharmacokinetics between mouse strains need to be considered in the design of experiments involving itraconazole treatment of mice experimentally infected with fungi.  (+info)

Efficacy of parenteral itraconazole against disseminated Candida albicans infection in two mouse strains. (2/89)

The efficacy of a new cyclodextrin intravenous formulation of itraconazole was evaluated by intraperitoneal treatment of experimental disseminated Candida albicans infections in BALB/c and DBA/2 mice. Mice were treated with doses of 5 or 20 mg/kg for 14 days and observation was continued for 28 days. Mice were randomly assigned to groups given either water or grapefruit juice as drinking fluid, since components of grapefruit juice that inhibit cytochrome P450 enzymes might influence the pharmacokinetic behaviour of itraconazole. The experiments showed that the itraconazole/cyclodextrin solution unequivocally prolonged survival and reduced weight loss over the first 4 days post-challenge, relative to placebo-treated control animals, in both mouse strains. However, the antifungal treatments did not reduce burdens of C. albicans in kidneys or brain. Placebo-treated DBA/2 mice given grapefruit juice to drink had a significantly shorter mean survival time than the equivalent group given water. In BALB/c mice the placebo-treated animals given grapefruit juice survived longer, though not significantly longer, than placebo-treated animals given water. These results give a preliminary hint that grapefruit juice alters the susceptibility of some mouse strains to C. albicans infection, regardless of any effects or non-effects it may have on itraconazole pharmacokinetics in the animals.  (+info)

Effects of bergamottin on human and monkey drug-metabolizing enzymes in primary cultured hepatocytes. (3/89)

We investigated the effect of bergamottin, a major furanocoumarin in grapefruit juice, on phase I and phase II drug-metabolizing enzymes using cultured human and monkey hepatocytes. Both cultured systems were compared and evaluated for the direct effects of bergamottin as well as control treatments on liver enzymes. Treatment of hepatocytes with 0.1, 1, 5, and 10 microM bergamottin resulted in a concentration-dependent reduction in CYP3A4 activity (40-100%) in both human and monkey cells, as measured by testosterone 6 beta-hydroxylase activity. Bergamottin was potent at eliciting these inhibitory effects at both basal and induced states of CYP3A. Bergamottin (5 microM) completely inhibited alpha-naphthoflavone-induced ethoxyresorufin O-dealkylase (EROD) and methoxyresorufin O-dealkylase (MROD) activities in human hepatocytes and caused a 100% decrease in EROD activity in monkey hepatocytes. A 48-h exposure of cultured human hepatocytes to bergamottin resulted in increased levels of immunoreactive CYP3A4, CYP1A1, and CYP1A2 proteins, and CYP3A4, CYP1A1, CYP1A2, CYP2B6, and UDP-glucuronosyl transferase mRNAs. There was only a 20 to 30% reduction in glucuronidation and sulfation of 4-methylumbelliferone in human hepatocytes by 10 microM bergamottin and no effect on conjugation in the monkey hepatocytes. These results suggest that bergamottin causes both inhibition of CYP3A and CYP1A1/2 enzymatic activities and induction of correspondent proteins and mRNAs.  (+info)

Effects of fragrance inhalation on sympathetic activity in normal adults. (4/89)

We investigated the effects of fragrance inhalation on sympathetic activity in normal adult subjects using both power spectral analysis of blood pressure fluctuations and measurement of plasma catecholamine levels. Fragrance inhalation of essential oils, such as pepper oil, estragon oil, fennel oil or grapefruit oil, resulted in 1.5- to 2.5-fold increase in relative sympathetic activity, representing low frequency amplitude of systolic blood pressure (SBP-LF amplitude), compared with inhalation of an odorless solvent, triethyl citrate (P<0.05, each). In contrast, fragrance inhalation of rose oil or patchouli oil caused a 40% decrease in relative sympathetic activity (P<0.01, each). Fragrance inhalation of pepper oil induced a 1.7-fold increase in plasma adrenaline concentration compared with the resting state (P = 0.06), while fragrance inhalation of rose oil caused a 30% decrease in adrenaline concentration (P<0.01). Our results indicate that fragrance inhalation of essential oils may modulate sympathetic activity in normal adults.  (+info)

Improving the mouse model for studying the efficacy of voriconazole. (5/89)

Outbred ICR mice were rendered neutropenic, infected intravenously with Fusarium solani and treated orally with voriconazole. When given alone, voriconazole was not protective up to 40 mg/kg/day. When grapefruit juice was administered before infection, mice were protected by voriconazole. The mechanism may be inhibition of gut mucosal cytochrome enzymes that rapidly degrade voriconazole in the mouse. These murine studies support expansion of voriconazole therapy in other highly resistant systemic mycoses.  (+info)

Antioxidative properties of Jaffa sweeties and grapefruit and their influence on lipid metabolism and plasma antioxidative potential in rats. (6/89)

The effective substances (polyphenols, phenolic and ascorbic acids, flavonoids and dietary fibers) and antioxidative activities, using different radical-scavenging tests, were determined for Jaffa sweeties and grapefruit. The antioxidative activities comprised the contributions from polyphenols, phenolic acids, flavonoids and ascorbate components, and were well-correlated with polyphenols and flavonoids. The correlation coefficient between the polyphenols and antioxidative activity varied from 0.73 to 0.99. All applied methods showed that sweeties had higher antioxidative activity than grapefruit. Experiments on laboratory animals show that diets supplemented with sweeties, and to a lesser extent with grapefruit, increased the plasma antioxidative potential and improved the lipid metabolism, especially in the rats fed with added cholesterol. These findings provide additional characterization of the nutritional value of citrus fruits and their influence on the lipid metabolism in rats.  (+info)

Grapefruit juice intake does not enhance but rather protects against aflatoxin B1-induced liver DNA damage through a reduction in hepatic CYP3A activity. (7/89)

Influence of grapefruit juice intake on aflatoxin B1 (AFB1)-induced liver DNA damage was examined using a Comet assay in F344 rats given 5 mg/kg AFB1 by gavage. Rats allowed free access to grapefruit juice for 5 days prior to AFB1 administration resulted in clearly reduced DNA damage in liver, to 65% of the level in rats that did not receive grapefruit juice. Furthermore, rats treated with grapefruit juice extract (100 mg/kg per os) for 5 days prior to AFB1 treatment also reduced the DNA damage to 74% of the level in rats that did not receive grapefruit juice. No significant differences in the portal blood and liver concentrations of AFB1 were observed between grapefruit juice intake rats and the controls. In an Ames assay with AFB1 using Salmonella typhimurium TA98, lower numbers of revertant colonies were detected with hepatic microsomes prepared from rats administered grapefruit juice, compared with those from control rats. Microsomal testosterone 6beta-hydroxylation was also lower with rats given grapefruit juice than with control rats. Immunoblot analyses showed a significant decrease in hepatic CYP3A content, but not CYP1A and CYP2C content, in microsomes of grapefruit juice-treated rats than in non-treated rats. No significant difference in hepatic glutathione S-transferase (GST) activity and glutathione content was observed in the two groups. GSTA5 protein was not detected in hepatic cytosol of the two groups. In microsomal systems, grapefruit juice extract inhibited AFB1-induced mutagenesis in the presence of a microsomal activation system from livers of humans as well as rats. These results suggest that grapefruit juice intake suppresses AFB1-induced liver DNA damage through inactivation of the metabolic activation potency for AFB1 in rat liver.  (+info)

CYP450 dietary inhibitors attenuate TNF-alpha-stimulated endothelial molecule expression and leukocyte adhesion. (8/89)

Enhanced expression of mucosal addressin cell adhesion molecule-1 (MAdCAM-1) and other endothelial cell adhesion molecules (ECAMs) are associated with the onset and progression of inflammatory bowel disease (IBD). We show in this study that two cytochrome p-450 (CYP450) inhibitors from Citrus paradis (grapefruit), bergamottin, and 6',7'-dihydroxybergamottin (DHB) block tumor necrosis factor (TNF)-alpha-stimulated expression of MAdCAM-1 in cultured endothelial cells and also reduce alpha(4)beta(7)-dependent lymphocyte adhesion. Bergamottin (20-50 microM) or DHB (10-30 microM) pretreatment dose-dependently reduced TNF-alpha-mediated expression of MAdCAM-1 and lymphocyte adhesion. Bergamottin and DHB also prevented expression of two other ECAMs, intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 (but not E-selectin). SKF-525a, a specific CYP450 inhibitor, also blocked the expression of MAdCAM-1 mediated by TNF-alpha. Similar to SKF-525a (20 microM), bergamottin (20 microM) and DHB (20 microM) directly inhibited the activity of CYP450 3A4. These results suggest that natural CYP450 inhibitors may be effective in reducing ECAM expression and leukocyte adhesion and therefore be useful in the clinical treatment of inflammatory states like IBD.  (+info)

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