The effect of grape seed and green tea extracts on the pharmacokinetics of imatinib and its main metabolite, N-desmethyl imatinib, in rats.

BACKGROUND: Imatinib is mainly metabolized by CYP3A4 and to a lesser extent by other isoenzymes, with N-desmethyl imatinib being its major equipotent metabolite. Being a CYP3A4 substrate, imatinib co-administration with CYP3A4 modulators would change its pharmacokinetic profile. The cancer chemoprevention potential and anticancer efficacy of many herbal products such as grape seed (GS) and green tea (GT) extracts had led to an increase in their concomitant use with anticancer agents. GS and GT extracts were demonstrated to be potent inhibitors of CYP3A4. The aim of this study is to investigate the effect of standardized GS and/or GT extracts at two different doses on the pharmacokinetics of imatinib and its metabolite, N-desmethyl imatinib, in SD-rats. METHODS: Standardized GS and/or GT extracts were administered orally once daily for 21 days, at low (l) and high (h) doses, 50 and 100 mg/kg, respectively, before the administration of a single intragastric dose of imatinib. Plasma samples were collected and analyzed for imatinib and N-desmethyl imatinib concentrations using LC-MS/MS method, then their non-compartmental pharmacokinetic parameters were determined. RESULTS: h-GS dose significantly decreased imatinib's Cmax and the [Formula: see text] by 61.1 and 72.2%, respectively. Similar effects on N-desmethyl imatinib's exposure were observed as well, in addition to a significant increase in its clearance by 3.7-fold. l-GT caused a significant decrease in imatinib's Cmax and [Formula: see text] by 53.6 and 63.5%, respectively, with more significant effects on N-desmethyl imatinib's exposure, which exhibited a significant decrease by 79.2 and 81.1%, respectively. h-GT showed similar effects as those of l-GT on the kinetics of imatinib and its metabolite. However, when these extracts were co-administered at low doses, no significant effects were shown on the pharmacokinetics of imatinib and its metabolite. Nevertheless, increasing the dose caused a significant decrease in Cmax of N-desmethyl imatinib by 71.5%. CONCLUSIONS: These results demonstrated that the pharmacokinetics of imatinib and N-desmethyl imatinib had been significantly affected by GS and/or GT extracts, which could be partially explained by the inhibition of CYP3A-mediated metabolism. However, the involvement of other kinetic pathways such as other isoenzymes, efflux and uptake transporters could be involved and should be characterized.

The effect of hawthorn flower and leaf extract (Crataegus Spp.) on cardiac hemostasis and oxidative parameters in Sprague Dawley rats.

Cardiovascular diseases are described as disorders of heart and vessels that involve stroke and coronary heart diseases. People in the Middle East converged to complementary medicine as an economic alternative to expensive healthcare services. Crataegus monogyna Jacq. (Lindm.) Rosacea is among the most commonly used herb for the treatment of declining cardiac performance, hypertension, and arrhythmias. Previously, we had shown that Crataegus Spp. (Hawthorn) extract increased the tendency of bleeding among patients undergoing coronary artery bypass grafting. Herein, the effects of Crataegus Spp. extract on oxidative stress, cardiac and hematological parameters were evaluated in Sprague Dawley rats. Male rats were randomly assigned into four groups. Group 1 served as control while groups 2-4 served as the experimental groups and were administered extract at doses of 100, 200, and 500 mg/kg. All the doses were given orally once/day and the treatment was continued for three weeks. Hawthorn treatment resulted in a significant decrease in the liver thiobarbituric acid reactive substances level in a dose-dependent manner compared to the control (1.258 (3, 24); P < 0.0001). We found a significant increase in the cardiac antithrombin III among hawthorn treated group compared to the control (4.18 (3, 24); P < 0.0001). On the other hand, hawthorn treatment decreased significantly the liver factor-X level (0.1341 (3, 22); P < 0.0001), while no significant changes were seen in soluble-platelet endothelial cell adhesion molecule-1 (P-value = 0.0599). In conclusions, hawthorn extract possesses an antioxidant effect and blood-thinning properties. Hence, we recommend attention when using this herbal extract with other anticoagulation and/or antiplatelet drugs or undergoing major cardiac surgery.

Development and Validation of a Rapid High-Performance Liquid Chromatography⁻Tandem Mass Spectrometric Method for Determination of Folic Acid in Human Plasma.

There are health concerns associated with increased folic acid intake from fortified food and supplements. Existing analytical methods, however, which can be employed to carry out epidemiological and bioavailability studies for folic acid involve laborious sample preparation and/or lengthy chromatographic analysis. In this paper we describe a simple, rapid, and sensitive high-performance liquid chromatography⁻electrospray ionisation-tandem mass spectrometry (HPLC⁻ESI-MS/MS) method for determination of unmetabolised folic acid in human plasma using folic acid-d4 as an internal standard. The method required only a simple sample preparation step of protein precipitation and had a total run time of 3.5 min, which is the shortest run time reported to date for HPLC⁻MS/MS method employed for quantifying folic acid in plasma. The analytes were separated on a C18 column (3 µm; 50 × 3.00 mm) using an isocratic mobile phase consisting of ammonium acetate (1 mM)-acetic acid-acetonitrile (9.9:0.1:90, v/v/v). The method was fully validated in terms of accuracy, precision, linearity, selectivity, recovery, matrix effect, and stability. The short run time and the minimal sample preparation makes the method a valuable tool for performing high-throughput analyses. To demonstrate the applicability of the method in real conditions, it was applied successfully in a bioavailability study for the determination of unmetabolised folic acid levels in vivo in human plasma after oral administration of folic acid.