喹禾灵对映体对斑马鱼毒性的手性选择性研究

为了研究喹禾灵对映体对水生生物的手性选择性毒性,对喹禾灵对映体进行了斑马鱼急性毒性试验,并研究了亚致死水平上对斑马鱼体内ATP酶活性的影响。研究发现,精喹禾灵和喹禾灵对斑马鱼的急性毒性分别为高毒和低毒;二者在诱导时间和诱导强度上对斑马鱼体内Na+,K+-ATP酶和Ca2+-ATP酶活性均表现出不同的作用方式。喹禾灵对斑马鱼Ca2+-ATP酶活性的影响在72 h时,250μg.L 1、1 000μg.L 12个处理组表现出明显诱导效应(P<0.05),在96 h各处理组均表现出诱导作用。精喹禾灵除在24 h时,5μg.L 1、10μg.L 1处理组外,其他各处理组对斑马鱼体内Ca2+-ATP酶表现出较强的诱导作用;72 h后,25μg.L 1、100μg.L 1处理组酶活性有下降趋势,其他2个处理组酶活性则继续增加。喹禾灵对斑马鱼Na+,K+-ATP酶活性的影响在48 h时,250μg.L 1、1 000μg.L 12个处理组有明显诱导效应(P<0.05),72 h时只有1 000μg.L 1处理组有明显诱导作用。精喹禾灵25μg.L 1、100μg.L 1处理组在24 h时对Na+,K+-ATP酶活性即表现出很强的诱导效果,48 h后各处理组酶活性都开始明显增加;72 h时各浓度处理组酶活性有下降趋势,96 h后基本与对照组无显著性差异。试验结果表明喹禾灵对映体对斑马鱼毒性有显著的手性选择性。     

Effect of age and gender in the pharmacokinetics of albendazole and albendazole sulphoxide enantiomers in goats

The kinetics of albendazole metabolites and albendazole sulphoxide enantiomers were studied in 2- and 14-month-old female and male goats, after a single oral dose administration (10 mg/kg) of an albendazole formulation. Blood samples from the jugular vein were collected at 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 42, 48 and 54 h post-treatment and analyzed using a high performance liquid chromatography method. In all groups the area under the plasma concentration-time curve (AUC) and peak concentration (C_max) values of (+)-ABZSO were significantly higher than those of (−)-ABZSO. The AUC and C_max values obtained for (+)-ABZSO and (−)-ABZSO in adult animals were higher compared to the results in young animals, showing significant differences except for (+)-ABZSO in female animals. In young animals, independently of gender, the C_max appeared earlier compared to adult animals. The mean residence time (MRT) values were shorter in young animals compared to adult animals for all compounds analyzed. No sex-related differences were found for any of the parameters calculated except for the (+)-ABZSO from adult animals.     

Variability in essential oil and bioactive chiral monoterpenoid compositions of Indian oregano (Origanum vulgare L.) populations from northwestern Himalaya and their chemotaxonomy

The chemical composition of essential oils isolated from aerial parts of native populations of Origanum vulgare L. from northwestern Himalaya was investigated by enantioselective gas chromatography (enantio-GC), capillary-gas chromatography (capillary-GC) and GC–MS. Seventy compounds, which accounted for 84.9–97% of the oil composition, have been identified. The oils were allotted to two main groups; the first group had a high percentage of components belonging to the thymol/carvacrol biosynthetic pathway and the second was characterized by a different sesquiterpene composition and a high linalool and bornyl acetate percentage. Essential oils of O. vulgare populations from Rilkot and Dhanachuli areas in northwestern Himalaya were characterized by high monoterpenoids proportions as compared to Nainital and Bhowali populations, which were dominated by sesquiterpenoids. High proportions of thymol (29.2–82%) were found only in two populations. Composition of the samples collected from Dhanachuli area differed from Nainital and Bhowali collections by a unique presence of carvacrol. Notably, there were significant differences in the concentration of rest of the terpenes in all the collections. On enantio-GC, enantiomeric excess for (3R) (−)- and (3S) (+)-linalool, (S) (+)- and (R) (−)-terpinen-4-ol, (S) (−)- and (R) (+)-α-terpineol, (1S) (−)-bornyl acetate and (1S) (−)-borneol were established in populations from Bhowali and Dhanachuli area. Moreover, linalool type oregano may be useful in promoting wider commercial utilization of the biodiversity of this species.     

Pharmacokinetics of albendazole sulfoxide enantiomers administered in racemic form and separately in rats

The pharmacokinetic behaviour of albendazole sulfoxide (ABZSO) enantiomers was studied in rats after the oral administration of 10 mg/kg of rac-ABZSO, 5 mg/kg of (-)-ABZSO or 5 mg/kg of (+)-ABZSO. The disposition profiles of ABZSO enantiomers were similar in all treatments, but the calculated area under the curve for the (-)-ABZSO was higher in all cases compared with (+)-ABZSO. The results suggest that there is no chiral inversion of ABZSO enantiomers. After the administration of rac-ABZSO, 17.2% of the total dose was recovered in urine as albendazole ABZ (0.1%), albendazole sulfone ABZSO(2) (0.3%), albendazole 2-aminosulfone (ABZ-SO(2)NH(2)) (3.1%) and ABZSO (13.7%). The ratio (+) to (-) was similar in urine (1.6) and blood (1.7).     

Species comparison of enantioselective oral bioavailability and pharmacokinetics of ketoprofen

As a part of ongoing research to further elucidate frequent and species-specific causes of differences in oral bioavailability, a 3 mg/kg dose of racemic ketoprofen, a high permeability/low solubility compound in the human biopharmaceutics classification system, was administered intravenously and orally to different species. Due to possible enantioselective disposition kinetics and inversion, enantiomers were quantitated separately using a stereospecific HPLC assay. The absolute bioavailability of R(−) and S(+) ketoprofen in chickens, turkeys, dogs and pigs was 31.5% and 52.6%, 42.6% and 32.5%, 33.6% and 89.1%, and 85.9% and 83.5% respectively. Incomplete bioavailability in poultry is probably due to incomplete absorption in addition to first-pass elimination. Low bioavailability of R(−) ketoprofen in dogs, strongly indicates first-pass metabolism. High bioavailability of S(+) ketoprofen in dogs and both enantiomers in pigs confirms that absorption of these substances is complete and controlled by gastric emptying rather than dissolution.     

Pharmacological assessment of netobimin as a potential anthelmintic for use in horses: Plasma disposition, faecal excretion and efficacy

This study aimed to determine the plasma disposition and faecal excretion of netobimin (NTB) and its respective metabolites as well as the efficacy against strongyles in horses following oral administration. Netobimin (10 mg/kg) was administered orally to 8 horses. Blood and faecal samples were collected from 1 to 120 h post-treatment and analysed by high performance liquid chromatography (HPLC). Using a chiral phase-based HPLC, plasma disposition of ABZSO enantiomers produced was also determined. Faecal strongyle egg counts (EPG) were performed by a modified McMaster’s technique before and after the treatment. Neither NTB nor ABZ were present and only albendazole sulphoxide (ABZSO) and sulphone metabolites (ABZSO₂) were detected in the plasma samples. Maximum plasma concentration of ABZSO (0.53 ± 0.14 μg/ml) and ABZSO₂ (0.36 ± 0.09 μg/ml) were observed at (t_max) 10.50 and 19.50 h, respectively following administration of NTB. The area under the curve (AUC) of the two metabolites was similar to each other. Netobimin was not detected, and ABZ was predominant in faecal samples. The maximum plasma concentration (C_max) of (−)ABZSO was significantly higher than (+)ABZSO, but the area under the curves (AUCs) of the enantiomer were not significantly different each other in plasma samples. The enantiomers of ABZSO were close to racemate in the faecal samples analyzed. Netobimin reduced the EPG by 100%, 100%, 77%, 80% and 75% 2, 4, 6, 8 and 10 weeks post-treatment, respectively. The specific behaviour of the two enantiomers probably reflects different enantioselectivity of the enzymatic systems of the liver which are responsible for sulphoxidation and sulphonation of ABZ. Considering the pharmacokinetic and efficacy parameters NTB could be used as an anthelmintic in horses.