Comparative pharmacokinetics of seven bioactive components in normal, sham-operated, and myocardial ischemia-reperfusion injury rats after oral administration of the Salvia Miltiorrhiza-Moutan Cortex herb pair.

Recently the Salvia Miltiorrhiza-Moutan Cortex (SM-MC) herb pair is considered as a promising Chinese medicinal mixture exhibiting a range of pharmacological activities, including treating cardiovascular disease due to its unique composition. In this study, we conducted the comparative pharmacokinetic analysis of seven main bioactive components of SM-MC in a different model rat. A straightforward ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) strategy that could simultaneously evaluate the levels of seven compounds was used to ensure the reliability of these pharmacokinetic analyses in rat plasma. The rat plasma samples were collected from normal, sham-operated, and myocardial ischemia-reperfusion injury (MIRI) groups at predetermined time points after the administration of SM-MC. The main pharmacokinetic parameters were detected and calculated. We successfully assessed the maximum concentration (Cmax ), time to Cmax (Tmax ), the elimination rate constant (λz ), total half-life (t1/2 ), total body clearance (CL), and the area under the concentration-time curve from 0 to last sampling time (AUC0-t ) and extrapolated to infinity (AUC0-∞ ). To sum up, an optimized UPLC-MS/MS approach that could be used to rapidly, simultaneously, and sensitively detect seven bioactive compounds derived from SM-MC extract preparations was successfully developed, which may offer a pharmacokinetic basis for preclinical and clinical studies of SM-MC herb pair for treating MIRI.

Pharmacokinetic behavior of peramivir in the plasma and lungs of rats after trans-nasal aerosol inhalation and intravenous injection.

Peramivir, a neuraminidase inhibitor, was approved globally and is indicated for the treatment of uncomplicated influenza in adults and children. However, the only approved intravenous formulation of peramivir limits its clinical application due to the need for the specialized dosing techniques and increases the risk of contracting influenza virus infection among healthcare professionals when dosing within a short distance to the patient. The purpose of this study was to investigate the pharmacokinetic profile of peramivir in plasma and the lung of rats and to compare the profiles following administration through trans-nasal aerosol inhalation (0.0888, 0.1776, and 0.3552 mg/kg) and intravenous injection (30 mg/kg). The plasma concentration reached the Cmax within 1.0 h (upon inhalation) and decreased at a t1/2 of 6.71 and 10.9 h after inhalation and injection, respectively. The absolute bioavailability of peramivir after inhalation was 78.2 %. Overall, the pharmacokinetic exposure of peramivir in the lungs was higher than that in the plasma after aerosol inhalation. After inhalation, the Cmax of peramivir in the lung was achieved within 1.0 h, and the elimination of the drug was slower than in the case of intravenous injection with t1/2 values 1.81 h for injection and 5.72, 53.5, and 32.1 h for low, middle, and high doses administered through inhalation. The Cmax and AUC0-t values for peramivir in the lungs increased linearly with the increased inhalation dose. The results elucidate the pharmacokinetic process of peramivir after trans-nasal aerosol inhalation to rats and provide useful information for further rational application of this drug formulation.

[PARTICIPATION OF AROMATIC MICROBIAL METABOLITES IN THE DEVELOPMENT OF SEVERE INFECTION AND SEPSIS.]

Background Actuality of the problem of infection in critically ill patients remains high. Addition a local infectious processes have a tendency to rapid generalization and sepsis. Neutrophilsfunction failure plays a key role in the patho- genesis of infectious complications and sepsis. The hypothesis about the role of microbial metabolites in the formation of immunosuppression, in particular in the inhibition of phagocytic activity of neutrophils as the first line of defense against bacteria is acquiring more and more supporters. Among the microbial metabolites aromatic compounds, such as phenylcarbinol acid (PCA) are of particular interest. Their concentration in the blood reaches a maximum in case of generalized infection, and correlates with mortality in patients in critical conditions, and PCA biological activity confirmed by earlier researches in vitro. The purpose of the study was to reveal the relationship of the PCA with the severity of bacterial infections and to assess the effect of PCA on neutrophils phagocytic activity. MATERIALS AND METHODS: At the first stage the levels of PCA (GCh-FID method) in the serum ofpatients (n=57) with a documented bacterial infection of varying severity, confirmed APACHE II and SOFA scales were analyzed comparing with healthy donors (n=72). During the second stage the effect of clinically-relevant concentrations of PCA on neutrophils phagocytic activity ofperipheral blood was analyzed in vitro. RESULTS: The levels ofphenylacetic (PAA), phenyllactic (PLA), hydroxyphenylacetic (p-HPAA) and hydroxyphenyllactic (p-HPLA) acids in patients were significantly higher than in healthy donors, reaching the highest values in severe infection. High direct correlation of PCA levels with the indicators ofscales APACHE II and SOFA was detected. A significant decrease in the number ofphagocytic neutrophils under the influence PAA, p-HPAA and PLA was identified in vitro experiment on average 11%. The most significant influence p-HPAA, PLA and p-HPLA have made on the intensity of the neutrophils absorption capacity reducing this parameter by an average of 26%. Also noted that phenylpropionic acid (PPC) which is in blood of healthy donors, disappears in critical ill patients. CONCLUSION: Phenolcarbonic acids level in the blood serum shows the severity of bacterial inflammatory process. Ex- periment in vitro shows that the PCA in clinically-relevant concentrations is able to suppress the neutrophilsphagocytic activity.

UHPLC-MS simultaneous determination and pharmacokinetic study of three aromatic acids and one monoterpene in rat plasma after oral administration of Shaofu Zhuyu decoction.

We developed a sensitive and rapid method for determination of ferulic acid, caffeic acid, vanillic acid, and paeoniflorin in rat plasma based on ultra high performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS). The separation of the four compounds was carried out on an AcQuity UHPLC™ BEH C18 column using a mobile phase consisting of acetonitrile and water (containing 0.1% formic acid). Electrospray ionization in positive and negative ion mode and multiple reaction monitoring was used to identify and quantify active components. All calibration curves gave good linearity (r > 0.991) over the concentration range from 4.24-2875 ngmL(-1) for all components. The precision of the in vivo study was evaluated by intraday and interday assays and the percentages of RSD were all within 10.6%. The recovery ranged from 60.2 to 77.9%. The method was successfully applied to pharmacokinetic study of all three aromatic acids and one monoterpene in rat plasma. Furthermore, we compared the pharmacokinetics profile of the four compounds in normal and primary dysmenorrhea rats' plasma following oral administration of Shaofu Zhuyu decoction (SFZYD) and its ethanol supernatant extract (SFE).

Phenolic acids are absorbed from the rat stomach with different absorption rates.

The intestinal absorption characteristics of phenolic acids (PAs) have been elucidated in terms of their affinity for the monocarboxylic acid transporter (MCT). Recently, the involvement of the stomach has been implicated in the absorption of polyphenols. The present work demonstrates that the gastric absorption efficiency of each PA is apparently different between various PAs. Various PAs with different affinities for MCT were administered (2.25 mumol) to rat stomach, and then the plasma concentration of the PA was measured. The plasma concentration of ferulic acid (FA) peaked 5 min after administration in the stomach. At 5 min after administration, the plasma concentration of each PA increased in the order: gallic acid = chlorogenic acid < caffeic acid < p-coumaric acid = FA. This order matches their respective affinity for MCT in Caco-2 cells, which we have demonstrated in previous studies. These results indicated that MCT might be involved in the gastric absorption of PAs, similar to the intestinal absorption.