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The xanthones α-mangostin and γ-mangostin are the major bioactive compounds in Garcinia mangostana (mangosteen) fruit extracts. Previously, we reported the pharmacokinetic properties of α-mangostin in rats. The purpose of this follow-up study was to compare the pharmacokinetic characteristics of α-mangostin and γ-mangostin in rats if administered as either a pure compound or as a component of a mangosteen fruit extract. The absolute bioavailability of γ-mangostin when administered as a pure compound was determined by giving male Sprague Dawley rats 2 mg/kg γ-mangostin intravenously or 20 mg/kg orally. A 160 mg/kg aliquot of mangosteen fruit extract was administered, containing α- and γ-mangostin doses equal to 20 mg/kg and 4.5 mg/kg of each pure compound, respectively. Plasma samples were collected for both pharmacokinetic studies, and compound concentrations were measured by LC-MS/MS. The pharmacokinetic of γ-mangostin after intravenous administration followed a two-compartment body model. The half-life of the distribution phase was 2.40 min, and that of the elimination phase was 1.52 h. After oral administration, both α- and γ-mangostin underwent intensive first-pass metabolism, and both compounds were conjugated rapidly after oral administration. When given as an extract, the total absorption of α- and γ-mangostin was not increased, but the conjugation was slower, resulting in increased free (unconjugated) compound exposure when compared to pure compound administration. Since reported beneficial biological activities of mangosteen xanthones are based on the free, unconjugated compounds, food supplements containing mangosteen fruit extracts should be preferred over the administration of pure xanthones.

The present study assessed the absolute and relative bioavailabilities of dodeca-2 E,4 E,8 Z,10 E/ Z-tetraenoic acid isobutylamides (tetraenes), the main bioactive constituents in Echinacea, administered as pure compounds or in the form of an Echinacea purpurea root extract preparation. Tetraenes were administered orally by gavage or intravenously in a dose of 0.75 mg/kg. The extract was administered orally in a dose of 158.6 mg/kg which corresponds to the same amount of tetraenes. Pharmacokinetic parameters of tetraenes were calculated by non-compartmental analysis using WinNonlin® 5.2 software. Mean dodeca-2 E,4 E,8 Z,10 E/ Z-tetraenoic acid isobutylamide dose-normalized plasma area under the concentration-time curve (AUC₀-∞/dose) was 3.24 ± 0.32 min · ng/mL/µg and 0.95 ± 0.16 min · ng/mL/µg after iv and oral administrations, respectively, and 1.53 ± 0.18 min · ng/mL/µg after oral administration of the Echinacea root extract. The absolute oral bioavailability of dodeca-2 E,4 E,8 Z,10 E/ Z-tetraenoic acid isobutylamides was 29.2 ± 2.3 %, which was increased to 47.1 ± 7.2 % (1.6-fold) by administration of the Echinacea extract. Administration of an Echinacea extract increased blood exposure with no impact on C(max), but prolonged the elimination half-life to 123.3 ± 15.7 min in comparison to 35.8 ± 6.5 min after administration of the pure dodeca-2 E,4 E,8 Z,10 E/ Z-tetraenoic acid isobutylamides.

The use of herbal supplements has increased steadily over the last decade. Recent surveys show that many people who take herbal supplements also take prescription and nonprescription drugs, increasing the risk for potential herb-drug interactions. While cytochrome P450-mediated herb-drug interactions have been extensively characterized, the effects of herbal extracts and constituents on UDP-glucuronosyl transferase (UGT) enzymes have not been adequately studied. Thus, the purpose of this review is to evaluate current evidence on the glucuronidation of phytochemicals and the potential for UGT-mediated herb-drug interactions with the top-selling herbal supplements in the United States and Europe. IN VITRO and animal studies indicate that cranberry, GINKGO BILOBA, grape seed, green tea, hawthorn, milk thistle, noni, soy, St. John's wort, and valerian are rich in phytochemicals that can modulate UGT enzymes. However, the IN VIVO consequences of these interactions are not well understood. Only three clinical studies have investigated the effects of herbal supplements on drugs cleared primarily through UGT enzymes. Evidence on the potential for commonly used herbal supplements to modulate UGT-mediated drug metabolism is summarized. Moreover, the need for further research to determine the clinical consequences of the described interactions is highlighted.

Valerenic acid (VA), a sesquiterpenoid, is one of the major secondary bioactive metabolites of VALERIANA OFFICINALIS L. Until now IN VIVO studies on the absorption, bioavailability, disposition, and metabolism of VA are limited. We established and validated an LC-MS/MS assay for the determination of VA in rat plasma and successfully used this method for pharmacokinetic studies in rats after intravenous (i. v.) and oral administrations. The plasma concentration-time data was analyzed by both non-compartmental and compartmental approaches using WinNonlin software. Following i. v. administration, the disposition of VA in rat plasma was biphasic, subdivided into a fast distribution and a slow elimination phase. The half-life of the distribution phase was 6-12 min, and that of the terminal elimination phase 6-46 h, indicating a possible large tissue binding. Disposition PK of valerenic acid after oral treatment was also described by a two-compartment model with a clearance (CL/F) of 2-5 L · h (-1) · kg (-1) and volume of distribution of (V (d)) 17-20 L · kg (-1). The extent of absorption (F) after oral administration was estimated to be 33.70 % with a half-life of 2.7-5 h. Dose proportionality was observed in terms of dose and AUCs, suggesting linear pharmacokinetics at the dose levels studied in rats.

The present study investigated the pharmacokinetics and tissue distribution of dodeca-2 E,4 E,8 Z,10 E/ Z-tetraenoic acid isobutylamides (tetraenes), the main alkamides in ECHINACEA preparations, in rats after a single oral dose administration of 2.5 mg/kg. Plasma, liver and 4 different brain regions (hippocampus, cerebral cortex, striatum and cerebellum) were collected after 8, 15, 30 minutes and 1, 2, 3 and 6 hours after oral dosing. Plasma and tissue concentrations were determined by a rapid (5 min) liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with benzanilide as internal standard (IS) using the respective [M-H] (+) ions, M/Z = 248/152 for the dodeca-2 E,4 E,8 Z,10 E/ Z-tetraenoic acid isobutylamides and M/Z = 198/105 for the IS. The lipophilic constituents were rapidly absorbed, with a T (max) of 15 minutes, distributed and appeared in the brain already within 8 minutes. The total amount of tetraenes in different brain parts was calculated as AUC (0-infinity) (range: 1764-6192 min x ng/g) and compared to the concentrations found in plasma (794 min x ng/mL) and liver tissues (1254 min x ng/g). The C (max) in plasma was 26.4 ng/mL, while the C (max) in the different brain regions varied between 33.8 ng/g and 46.0 ng/g. In the striatum the highest concentration and the longest elimination half-life of 253 minutes with a mean residence time of 323 minutes was detected. The results demonstrate that the dodeca-2 E,4 E,8 Z,10 E/ Z-tetraenoic acid isobutylamides are bioavailable in rats with a rapid passage across the blood-brain barrier.

Since data concerning the toxicity and pharmacokinetics of concomitant repeated administration of grapefruit juice (GFJ) and simvastatin are lacking, we performed a chronic study in rats over a 4-week period using two different strengths (regular [RS] and double strength [DS]) of GFJ and two different doses of simvastatin (20 and 80 mg/kg, respectively). Both juices did not have a significant effect on the pharmacokinetic parameters of either simvastatin lactone (SVL) or its active metabolite simvastatin hydroxy acid (SVA) when administered concomitantly in a dose of 20 mg/kg over 28 days. However, when administered with 80 mg/kg simvastatin concentrations were elevated up to the last day of the study with DS-GFJ and to a lesser extent with RS-GFJ. Evaluation of toxicological parameters revealed a significant decrease in body and liver weights in groups receiving 20 mg/kg or 80 mg/kg simvastatin alone as well as in groups receiving simvastatin concomitantly with either DS- or RS-GFJ. No significant differences were detected for alanine (ALT) and aspartate (AST) aminotranferases in all groups. Chronic treatment with simvastatin significantly decreased plasma cholesterol levels (18 % for 20 mg/kg, 19 % for 80 mg/kg, respectively) as did coadministration of 80 mg/kg simvastatin with either RS-GFJ or DS-GFJ (33 %, 16 %). Interestingly, treatment with RS- or DS-GFJ alone significantly decreased plasma cholesterol levels by 22 % and 30 %, respectively. In conclusion, our results suggest that toxic effects in rats of concomitant intake of simvastatin and GFJ over 28 days are not more pronounced than those of simvastatin alone and that dose relationships between the administration of the juice and the drug may be important in determining the magnitude of the interaction.