Abstract:TM-2 is a novel semi-synthetic taxane derivative, selected for preclinical development based on its greater anticancer activity and lower toxicity compared with docetaxel. In this study, a rapid and sensitive analytical method based on ultra performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) has been developed for the determination of TM-2 in rat plasma. The biological samples were extracted with methyl tert-butyl ether and separated on a C18 column (50 mm × 2.1 mm, 1.7 µm) using a mobile ph… Show more
“…There are some researches on derivative compounds from taxanes, such as DTX, TM-2 and Larotaxel [27] , [28] , [29] . Compared with DTX, 6258-70 has a longer t 1/2 and a higher CL z [20] .…”
Cancer is the leading cause of death all over the world. Among the chemotherapy drugs, taxanes play an important role in cancer treatment. 6258-70 is a new semi-synthetic taxane which has a broad spectrum of antitumor activity. A fast and reliable high performance liquid chromatography-tandem mass spectrometry (HPLC–MS/MS) method was developed for quantification of 6258-70 in rat plasma and tissues in this paper. After extraction by liquid-liquid extraction method with methyl tert-butyl ether, the samples were separated on a Kinetex C18 column (50 mm×2.1 mm, 2.6 µm, Phenomenex, USA) within 3 min. The method was fully validated with the matrix effect between 87.7% and 99.5% and the recovery ranging from 80.3% to 90.1%. The intra- and inter-day precisions were less than 9.5% and the accuracy ranged from −3.8% to 6.5%. The reliable method was successfully applied to the pharmacokinetics and tissue distribution studies of 6258-70 after intravenous administration in rats. The pharmacokinetic results indicated that the pharmacokinetic behavior of 6258-70 in rats was in accordance with linear features within tested dosage of 1 to 4 mg/kg, and there was no significant difference between the two genders. The tissue distribution study showed that 6258-70 had an effective penetration, spread widely and rapidly and could cross blood-brain barrier. The results of pharmacokinetics and tissue distribution may provide a guide for future study.
“…There are some researches on derivative compounds from taxanes, such as DTX, TM-2 and Larotaxel [27] , [28] , [29] . Compared with DTX, 6258-70 has a longer t 1/2 and a higher CL z [20] .…”
Cancer is the leading cause of death all over the world. Among the chemotherapy drugs, taxanes play an important role in cancer treatment. 6258-70 is a new semi-synthetic taxane which has a broad spectrum of antitumor activity. A fast and reliable high performance liquid chromatography-tandem mass spectrometry (HPLC–MS/MS) method was developed for quantification of 6258-70 in rat plasma and tissues in this paper. After extraction by liquid-liquid extraction method with methyl tert-butyl ether, the samples were separated on a Kinetex C18 column (50 mm×2.1 mm, 2.6 µm, Phenomenex, USA) within 3 min. The method was fully validated with the matrix effect between 87.7% and 99.5% and the recovery ranging from 80.3% to 90.1%. The intra- and inter-day precisions were less than 9.5% and the accuracy ranged from −3.8% to 6.5%. The reliable method was successfully applied to the pharmacokinetics and tissue distribution studies of 6258-70 after intravenous administration in rats. The pharmacokinetic results indicated that the pharmacokinetic behavior of 6258-70 in rats was in accordance with linear features within tested dosage of 1 to 4 mg/kg, and there was no significant difference between the two genders. The tissue distribution study showed that 6258-70 had an effective penetration, spread widely and rapidly and could cross blood-brain barrier. The results of pharmacokinetics and tissue distribution may provide a guide for future study.
“…In order to determine the plasma protein binding rates, the equilibrium dialysis method was used. TM-2 at different designed concentrations (50, 500, 2000 ng/mL for rat, 50, 200, 1000 ng/mL for human and 50, 200, 500 ng/mL for beagle dog, the concentrations were designed depending on the peak concentration, distribution phase concentration and elimination phase concentration in rats and beagle dog [4] , [6] ) was in-vitro spiked to the PBS buffer and the blank rat, human or beagle dog plasma was added into the semi-permeable membrane bag. Prior to analysis, each of the resulting samples was incubated at 37 °C for 24 h to achieve equilibrium between plasma and PBS buffer.…”
Section: Methodsmentioning
confidence: 99%
“…The pharmacokinetic studies of TM-2 in both rats and dogs have also been studied. Also, the major metabolic pathway of TM-2 in rats was hydroxylation of the taxane ring or the lateral chain [4] , [5] , [6] , [7] . Fig.…”
TM-2 known as a potential antitumor drug is a novel semi-synthetic taxane derivative. As drug–protein interactions contribute to insights into pharmacokinetic and pharmacodynamic properties, we elucidated the binding of TM-2 to plasma protein. In this study, a simple, rapid and reliable method was developed and validated employing equilibrium dialysis for the separation of bound and unbound drugs and ultra-performance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) for the quantitation. Protein binding reached equilibrium within 24 h of incubation at 37 °C. After liquid–liquid extraction with methyl tert-butyl ether, the samples were separated on Thermo Syncronis UPLC® C18 (2.1 mm×50 mm, 1.7 µm), and acquisition of mass spectrometric data was performed in multiple reaction monitoring (MRM) mode via positive electrospray ionization. The assay was linear over the concentration rang of 5–2000 ng/mL. The intra- and inter-day precisions were 0.1%–14.8%, and the accuracy was from −6.4% to 7.0%. This assay has been successfully applied to a protein binding study of TM-2 in rat, human and beagle dog plasma. TM-2 showed high protein binding of 81.4%±6.5% (rat), 87.9%±3.6% (human) and 79.4%±4.0% (beagle dog). The results revealed that there was an insignificant difference among the three species.
“…However, the acquired and intrinsic tumor resistance of paclitaxel and docetaxel affects their clinical efficacy (2). TM-2, a paclitaxel derivative, has a modification at C-3'that would inhibit the P-glycoprotein expression to reduce cellular efflux activity (3) and was considered to possess higher anti-tumor activity compared to docetaxel (4). The poor aqueous solubility of paclitaxel and its derivatives limited their clinical applications.…”
Purpose This study aims to investigate the effect of poly(D, Llactic acid) 10K (PDLLA 10K ) incorporation on the drug loading and stability of poly(ethylene glycol) 2K -block-poly(D, Llactide) 2.4K (mPEG 2k -b-PDLLA 2.4k ) micelles. In addition, a suitable lyophilization protector was screened for this micelle to obtain favorable lyophilized products. Methods The incorporation ratios of PDLLA 10k were screened based on the particle size and drug loading. The dynamic stability, core viscosity, drug release, stability in albumin, and in vivo pharmacokinetic characteristics of PDLLA 10k incorporated micelles were compared with the original micelles. In addition, the particle size variation was used as an indicator to screen the most suitable lyophilization protectant for the micelles. DSC, FTIR, XRD were used to illustrate the mechanism of the lyophilized protectants. Results After the incorporation of 5 wt% PDLLA 10K , the maximum loading of mPEG 2k -b-PDLLA 2.4k micelles for TM-2 was increased from 26 wt% to 32 wt%, and the in vivo half-life was increased by 2.25-fold. Various stability of micelles was improved. Also, the micelles with hydroxypropyl-β-cyclodextrin (HP-β-CD) as lyophilization protectants had minimal variation in particle size. Conclusions PDLLA 10k incorporation can be employed as a strategy to increase the stability of mPEG 2k -b-PDLLA 2.4k micelles, which can be attributed to the viscosity building effect. HP-β-CD can be used as an effective lyophilization protectant since mPEG and HP-β-CD form the pseudopolyrotaxanesque inclusion complexes.
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