Sex dependent pharmacokinetics,tissue distribution and excretion of peimine and peiminine in rats assessed by liquid chromatography–tandem mass spectrometry

Ethnopharmacological relevance

Fritillaria thunbergii Miq. has been traditionally used in China as antitussive and expectorant herbs, and newly used in the clinical treatment of leukemia in recent years.

Aim

To investigate whether gender exerted a significant influence on the pharmacokinetics, tissue distribution and excretion of peimine and peiminine in Sprague-Dawley rats who were given a single oral administration of 4.25 g/kg Fritillaria thunbergii Miq. extract.

Materials and methods

Sprague-Dawley rats were assigned into two groups based on the gender and orally administered 4.25 g/kg Fritillaria thunbergii Miq. extract for each individual pharmacokinetics, tissue distribution and excretion study.

Results

Compared with female rats, peimine and peiminine were eliminated slowly from male rat plasma, and significant gender-related differences were observed in the pharmacokinetic parameters. Drug blood and tissue levels in male rats were significantly higher than the female counterparts except for several tissues, such as fat, muscle and skin. Gender also exerted a significant influence on the urine excretion but such effect was not observed in the feces excretion study.

Conclusions

Gender exerted a significant influence on the pharmacokinetics, tissue distribution and urine excretion of peimine and peiminine. It is assumed that the sex-associated differences of peimine and peiminine in rats might be mainly result from sex-dependent expression and activity of drug metabolism enzymes and P-glycoprotein.     

皂苷类成分吸收分布和代谢及排泄研究进展

皂苷是一类具有多种药理活性的重要天然产物,但由于其生物利用度普遍较低,体内的药效物质基础和作用机制研究尚不够深入,影响了该类成分的新药开发与应用。本文对近年来国内外关于皂苷类化合物体内外代谢等过程研究的文献进行综述,有利于深入探索该类成分的体内药效物质基础和作用机制,为新药研发提供一定的理论依据。     

Pharmacokinetics and metabolism of the dipeptidyl peptidase IV inhibitor carmegliptin in rats,dogs, and monkeys

1. The pharmacokinetics and excretion of carmegliptin, a novel dipeptidyl peptidase IV inhibitor, were examined in rats, dogs, and cynomolgus monkeys.

2. Carmegliptin exhibited a moderate clearance, extensive tissue distribution, and a variable oral bioavailability of 28–174%. Due to saturation of intestinal active secretion, the area under the plasma concentration–time curve (AUC) in dogs and monkeys increased in a more than dose-proportional manner over an oral dose range of 2.5–10?mg/kg.

3. Following oral administration of [¹⁴C]carmegliptin at 3?mg/kg, >?94% of the radioactive dose was recovered in 72-h post-dose from Wistar rats and Beagle dogs. Virtually, the entire administered radioactive dose was excreted unchanged in urine, intestinal lumen, and bile. Approximately 36%, 29%, and 19% of the dose were excreted by respective routes. Consistently, in vitro, carmegliptin was highly resistant to hepatic metabolism in all species tested.

4. Based on in vitro studies, carmegliptin is a good substrate for Mdr1/MDR1. Breast cancer resistance protein (Bcrp) is not expected to be involved in the transport of carmegliptin since in vitro carmegliptin was not significantly transported by this transporter.

5. The very high extravascular distribution of carmegliptin in the intestinal tissues, as demonstrated in Wistar rats and Beagle dogs, could play a significant role in its therapeutic effect.

     

Pharmacokinetics and Excretion Studies on CDRI-85/92, an Antiulcer Proton Pump Inhibitor

CDRI 85/92 is an antiulcer pharmacophore and a proton pump inhibitor, which is in an advanced stage of preclinical trials. In view of its importance, pharmacokinetic and excretion were studied in Sprague Dawley rats after administering 20 mg/kg oral and intravenous doses. The compound was detectable in the serum samples as early as 5 min post-oral administration. The compound was eliminated slowly from serum with an elimination half-life of 2.1 h. Following the 20 mg/kg oral dose, maximum serum concentration (C(max)) was found to be 469.28 ± 45.52 ng/ml after 1.0 h. Based on AUC values, the absolute bioavailability of the CDRI 85/92 was 70.5% after oral administration. It was found to be excreted in urine (~15% of the dose) in intravenously treated (bile duct cannulated as well as noncannulated) rats, whereas bile and feces depicted insignificant levels of the compound.     

肾脏转运体及其研究方法

肾脏是机体重要器官之一,主要承担着体内代谢产物、药物以及毒物等物质的排泄。因此明确各物质在肾脏排泄机制有利于提高药物的安全性,避免不良反应,可为指导临床合理用药提供理论依据。本文介绍了肾脏中介导药物分泌与重吸收的转运体,阐述了通过体内、体外方法预测药物经肾脏转运体在肾脏的转运以及排泄机制。此外,还概括了研究肾脏转运体的主要研究方法,为基础以及临床实验提供参考。     

The metabolism and disposition of GSK2140944 in healthy human subjects

1.?GSK2140944 is a novel bacterial topoisomerase inhibitor in development for the treatment of bacterial infections. The metabolism and disposition in healthy human subjects was investigated.

2.?Six male subjects received [¹⁴C] GSK2140944 orally (2000?mg) and as a single 2-hour i.v. infusion (1000?mg). Urinary elimination (59%) was major by the i.v. route, whereas fecal elimination (53%) pre-dominated via the oral route. Accelerator mass spectrometry (AMS) was used for the analysis of plasma and bile samples due to the low level of radioactivity in samples (low specific activity of the doses). Unchanged GSK2140944 was the predominant circulating component (>60% DRM), with the main circulating metabolite M4 formed by oxidation of the triazaacenaphthylene moiety representing 10.8% (considered major) and 8.6% drug-related material by the oral and i.v. route, respectively. Approximately 50% of the oral dose was absorbed and eliminated mainly as unchanged GSK2140944 in urine (～20% of dose). Elimination via metabolism (～13% of dose) was relatively minor. The facile oxidation of GSK2140944 to metabolite M4 was believed to be a result of activation by adjacent electron withdrawing groups.

3.?This study demonstrates the use of AMS to overcome radioprofiling challenges presented by low specific activity resulted from high doses administration.     

The effect and fate of water-soluble carbon nanodots in maize (Zea mays L.)

In this study, the toxicity of water-soluble carbon nanodots (C-dots) to maize (Zea mays L.) and their uptake and transport in plants were investigated. After exposed in sand matrix amended with 0–2000?mg/L C-dots for 4 weeks, we found that the phytotoxicity of C-dots was concentration-dependent. C-dots at 250 and 500?mg/L showed no toxicity to maize. However, 1000 and 2000?mg/L C-dots significantly reduced the fresh weight of root by 57% and 68%, and decreased the shoot fresh weight by 38% and 72%, respectively. Moreover, in maize roots, the exposure of C-dots at 2000?mg/L significantly increased the H₂O₂ content and lipid peroxidation (6.5 and 1.65 times higher, respectively), as well as, the antioxidant enzymes activities, up to 2, 1.5, 1.9 and 1.9 times higher for catalase, ascorbate peroxidase, guaiacol peroxidase and superoxide dismutase, respectively. On the other hand, C-dots were observed in detached root-cap cells, cortex and vascular bundle of roots and mesophyll cells of leaves through fluorescence microscopy analysis, suggesting that C-dots were absorbed and translocated systemically in maize. Remarkably, a certain amount of C-dots were excreted out from leaf blade. To our knowledge, this is the first study combined phenotypic observation with physiologic responses and bioaccumulation and translocation analysis of C-dots to investigate their effect and fate in maize.     

盐酸他可林在大鼠体内的分布和排泄

目的 研究盐酸他可林（ＴＨＡ）在大鼠体内的分布和排泄。方法 大鼠以剂量８ｍｇ／ｋｇ灌胃给予盐酸他可林后，在规定时间摘取各脏器，收集尿粪，提取后用高效液相法测定浓度，分别计算药物在各组织的分布和排泄。结果 ６９％的药物由尿排泄，２４％的药物由粪排泄。在尿粪中原形药ＴＨＡ仅占３．１％。而１－ＯＨ－ＴＨＡ和２－ＯＨ－ＴＨＡ分别为４２．０％放３５．５％，结论 盐酸他可林在大鼠体内的清除途径以羟代谢为主，药     

Tributyltin-binding protein type 1 has a distinctive lipocalin-like structure and is involved in the excretion of tributyltin in Japanese flounder, Paralichthys olivaceus

Tributyltin-binding protein type 1 (TBT-bp1) is a newly discovered protein that binds with TBT in the blood of the Japanese flounder, Paralichthys olivaceus. We determined the genomic sequence of TBT-bp1 and found that this protein has a conserved exon–intron structure that is common to the lipocalin protein family. The secondary and tertiary structures of TBT-bp1, predicted from amino acid sequence, included at least two α-helices and eight β-sheets that are conserved in all lipocalins and form a barrel structure that may bind with ligands. Analysis of the gene structure, secondary structure, and tertiary structure demonstrated that TBT-bp1 could be classified as a lipocalin. A homology search revealed the presence of TBT-bp1-like proteins in eight species of teleost. When flounder were injected intraperitoneally with TBT-d27 at 11.6 μg/fish, TBT-d27 was detected in the blood and in the skin mucus. The concentration of TBT-d27 in mucus was approximately 1/100 of that in the serum. Western blotting analysis revealed that TBT-bp1 was present in the skin mucus. These results suggest that TBT-bp1 in Japanese flounder binds with TBT and is excreted from the body via the mucus.     

[~3H]十一酸睾丸素肌注后在大鼠的吸收、分布和排泄

大鼠肌注[~3H]十一酸睾丸素油剂,血浆放射峰在药后2d 出现,32d和60d 的血浆放射性分别为峰值的13.3%及9.9%,放射性的分布以肝、肾、脂肪为高,次为提肛肌、附睾、睾丸、前列腺与储精囊。药后60d,肌注部位残留放射性为给药量的19.9%;尿和粪中放射性累积排泄量分别为给药量的41.4%和9.3%。算得 t_((1/2)ka)=6.9d;t_((1/2)α)=6.9d;t_((1/2)β)=15.4d。