Pharmacokinetic study comparing pure desoxo-narchinol A and nardosinonediol with extracts from Nardostachys jatamansi.

Nardostachyos Radix et Rhizoma (NR) is a valuable medicinal herb widely used in Korea, India, and China for the treatment of many diseases. Desoxo-narchinol A (DA) and nardosinonediol (ND) are the two main bioactive compounds belonging to the sesquiterpene group. Desoxo-narchinol A possesses anti-inflammatory activity while ND exhibits anti-depressant and cardioprotective activities. A pharmacokinetic study is important to decide whether the isolated compounds or the NR extract have better pharmacological activity. Hence, we developed an analytical method for studying the pharmacokinetics of DA and ND after oral administration of the pure compounds and herbal extract. An optimized liquid chromatography-mass spectrometry method (LC-MS/MS) with solid-phase extraction (SPE) for sample preparation was developed. A ZORBAX Extend C18 column (2.1 × 50 mm, 3.5 µm) was used under gradient elution with acetonitrile and 0.1% formic acid in water as the mobile phase. Validation experiments assessing accuracy, precision, and stability were satisfactory; the lower limit of quantification was 5 ng/mL. For the pharmacokinetic study, three groups of rats were administrated pure DA, pure ND, or NR extract orally. Concentrations of DA and ND in their plasma were determined by the developed method. Pharmacokinetic parameters, including the time to achieve maximum plasma concentration (Tmax) and the area under the plasma concentration curve from time zero to infinity (AUC0-∞), were compared for the herbal extract and pure compounds. The Tmax of the pure compound and the NR extract for DA was 7.50 and 8.33 min, respectively, compared to 5.00 and 5.83 min for the pure compound and the NR extract for ND, respectively. The AUC0-∞ of the pure compound and the NR extract for DA was 156.34 and 133.90 µg min/mL, respectively, and that for the NR extract for ND was 6.42 and 4.15 µg min/mL, respectively. LC-MS/MS was used to determine DA and ND in rat plasma. The pharmacokinetic profile of each pure compound and those in the extract were characterized and compared.

Pharmacokinetic profiles of falcarindiol and oplopandiol in rats after oral administration of polyynes extract of Oplopanax elatus.

Polyynes, such as facarindiol (FAD) and oplopandiol (OPD), are responsible for anticancer activities of Oplopanax elatus (O. elatus). A novel approach to pharmacokinetics determination of the two natural polyynes in rats was developed and validated using a liquid chromatography-electrospray ionization-mass spectrometry (LC-MS) method. Biosamples were prepared by liquid-liquid extraction using ethyl acetate/n-hexane (V : V = 9 : 1) and the analytes were eluted on an Agilent ZORBAX Eclipse Plus C18 threaded column (4.6 mm × 50 mm, 1.8 µm) with the mobile phase of acetonitrile-0.1% aqueous formic acid at a flow-rate of 0.5 mL·min(-1) within a total run time of 11 min. All analytes were simultaneously monitored in a single-quadrupole mass spectrometer in the selected ion monitoring (SIM) mode using electrospray source in positive mode. The method was demonstrated to be rapid, sensitive, and reliable, and it was successfully applied to the pharmacokinetic studies of the two polyynes in rat plasma after oral administration of polyynes extract of O. elatus.

Application of a sensitive and specific LC-MS/MS method for determination of chinensinaphthol methyl ether in rat plasma for a bioavailability study.

Chinensinaphthol methyl ether (CME) is a potential pharmacologically active ingredient isolated from the dried plants of Justicia procumbens L. (Acanthaceae). A sensitive and specific LC-MS/MS method was developed and validated for the analysis of CME in rat plasma using buspirone as the internal standard (IS). The analyte was extracted with ethyl acetate and chromatographed on a reverse-phase Agilent Zorbax-C18 110 Å column (50 mm × 2.1mm, 3.5 µm). Elution was achieved with a gradient mobile phase consisting of water and acetonitrile both containing 0.1% formic acid at a flow rate of 0.40 mL/min. The analytes were monitored by tandem-mass spectrometry with positive electrospray ionization. The precursor/product transitions (m/z) in the positive ion mode were 394.5→346.0 and 386.1→122.0 for CME and IS, respectively. The assay was shown to be linear over the range of 0.50-500 ng/mL, with a lower limit of quantification of 0.50 ng/mL. The method was shown to be reproducible and reliable with the inter- and intra-day accuracy and precision were within ±15%. The assay has been successfully used for pharmacokinetic evaluation of CME after intravenous and oral administration of 1.80 mg/kg CME in rats. The oral absolute bioavailability (F) of CME was estimated to be 3.2±0.2% with an elimination half-life (t½) value of 2.4±0.8h, suggesting its poor absorption and/or strong metabolism in vivo.

Pomegranate juice inhibits sulfoconjugation in Caco-2 human colon carcinoma cells.

Several fruit juices have been reported to cause food-drug interactions, mainly affecting cytochrome P450 activity; however, little is known about the effects of fruit juices on conjugation reactions. Among several fruit juices tested (apple, peach, orange, pineapple, grapefruit, and pomegranate), pomegranate juice potently inhibited the sulfoconjugation of 1-naphthol in Caco-2 cells. This inhibition was both dose- and culture time-dependent, with a 50% inhibitory concentration (IC(50)) value calculated at 2.7% (vol/vol). In contrast, no obvious inhibition of glucuronidation of 1-naphthol in Caco-2 cells was observed by any of the juices examined. Punicalagin, the most abundant antioxidant polyphenol in pomegranate juice, was also found to strongly inhibit sulfoconjugation in Caco-2 cells with an IC(50) of 45 microM, which is consistent with that of pomegranate juice. These data suggest that punicalagin is mainly responsible for the inhibition of sulfoconjugation by pomegranate juice. We additionally demonstrated that pomegranate juice and punicalagin both inhibit phenol sulfotransferase activity in Caco-2 cells in vitro, at concentrations that are almost equivalent to those used in the Caco-2 cells. Pomegranate juice, however, shows no effects on the expression of the sulfotransferase SULT1A family of genes (SULT1A1 and SULT1A3) in Caco-2 cells. These results indicate that the inhibition of sulfotransferase activity by punicalagin in Caco-2 cells is responsible for the reductions seen in 1-naphthyl sulfate accumulation. Our data also suggest that constituents of pomegranate juice, most probably punicalagin, impair the enteric functions of sulfoconjugation and that this might have effects upon the bioavailability of drugs and other compounds present in food and in the environment. These effects might be related to the anticarcinogenic properties of pomegranate juice.

S-8921 (Shionogi).

S-8921 is a sodium/bile acid transport inhibitor under development by Shionogi for the potential treatment of hyperlipidemia. As of June 2000, phase I trials had commenced in Japan and were planned in Europe [370602]. S-8921 acts by altering sodium-dependent transport mechanisms of the brush-borders in the intestinal mucosa, causing bile acids that re-enter the intestine to be excreted rather than reabsorbed [281476].

Pharmacokinetics of 2-naphthol following intrapericardial administration, and formation of 2-naphthyl-beta-D-glucoside and 2-naphthyl sulphate in the American lobster, Homarus americanus.

1. Following a 0.25-mg/kg intrapericardial dose of the phenolic compound, 2-naphthol, to the American lobster, Homarus americanus, a two-compartment model best described the disposition of parent [14C]-2-naphthol in the haemolymph. Male and female lobsters had similar alpha-phase half lives of 26 +/- 19 min (mean +/- SD, n = 4) and 29 +/- 15 min respectively. The beta-phase half lives were significantly longer in males, 63.9 +/- 30.9 h, than in females, 30.6 +/- 6.8 h (p < 0.05). The total body clearance for females was 26.4 +/- 6.5 ml x h-1 x kg-1 and was higher than that of males, 11.1 +/- 5.9 ml x h-1 x kg-1 (p < 0.05). 2. 2-Naphthol was converted to 2-naphthyl-beta-D-glucoside (major metabolite) and 2-naphthyl sulphate (minor metabolite) such that at 24 h 39-60.6% of the radioactivity in haemolymph was 2-naphthyl-beta-D-glucoside, 38.6-58.9% 2-naphthol and 0.5-4% 2-naphthyl sulphate. 3. The 2-naphthol-derived radioactivity was > 99% bound to haemolymph proteins at 1 min and > 90% bound at 1 day after the dose, indicating that both 2-naphthol and 2-naphthyl-beta-D-glucoside were highly protein bound. 4. 2-Naphthyl-beta-D-glucoside was slowly eliminated from haemolymph in both males and females, with elimination half lives of 34-78 h. 2-Naphthyl-beta-D-glucoside was the major metabolite in urine samples collected at 5 days after the dose. Hepatopancreas and antennal gland contained glucosidase activities, and the long half life of 2-naphthyl-beta-D-glucoside could be explained by conjugation deconjugation cycling. 5. 2-Naphthyl sulphate was eliminated from haemolymph with a half-life < 10 h and was excreted in urine.