An HPLC Method for Determination of a New Diorganotin(IV) Benzohydroxamate in Rat Plasma and Its Application to Pharmacokinetic Studies

Abstract

n-Bu) 2 Sn{4-ClC 6 H 4 C(O)NHO} 2 ] (DBDCT) is a new diorganotin(IV) benzohydroxamate which shows high in vivo antitumor activity with relative low toxicity. An HPLC method for the determination of diorganotin(IV) benzohydroxamate (DBDCT) was first validated in the pharmacokinetic studies in plasma. The rat plasma was deproteinized with methanol that contained acetanilide as the internal standard and then separated. The HPLC assay was carried out using a Diamonsil ODS (4.6 mm×200 mm, 5 µm) column. The mobile phase was methanol and 0.5% trifluoroacetic acid (TFA) in water (30∶70, V/V, pH 3.0) with a flow rate of 1.0 mL•min -1 . The detection wavelength was set at 238 nm. This method was found to be linear within the concentration range of 0.1-25 µg•mL -1 (r＝0.9992). The limit values of quantification and detection were 50 and 10 ng•mL -1 , respectively. The method was used to determine the concentration-time profiles for DBDCT in the plasma after single intravenous administration with different doses to rats (2, 5, 12 mg•kg -1 ). The pharmacokinetics parameter calculations and modeling were carried out using the 3p97 pharmacokinetics software. The results showed that the concentration-time curve of DBDCT in rat plasma could be fitted to the two-component model.

Preparation, antitumor activity in mice, pharmacokinetics and tissue distribution in rats of di‐n‐butyl‐di‐(4‐chlorobenzohydroxamato)tin(IV) liposome

“…100 µl acetanilide (2.5 µg ml −1 ) and 100 µl methanol were added to 100 µl samples, respectively. After the samples were vortexed for 3 min, the mixture was centrifuged at 13 000 × g for 5 min at 4 °C and the supernatant was extruded through membranes of 0.45 µm pore size …”

“…Compared to free DBDCT, DBDCT‐L had lower Cl. Our previous studies showed that the free DBDCT was eliminated quickly in blood, 2 h later . In this study, according to the data shown above, DBDCT‐L obviously prolonged the residence time and improved the concentration of DBDCT in the blood circulation system.…”

“…Reducing this adverse effect while maintaining antitumor activity constitutes a difficult problem that many anticancer drugs urgently await to be solved. Our recent study showed that, like other diorganotin(IV) complexes, DBDCT could distribute and be eliminated rapidly in rats with a short T 1/2 value . Unfortunately, however, DBDCT also showed notable toxicity in many rat tissues, especially in the central nervous system and liver, based on our previous studies .…”

“…Our previous studies showed that DBDCT could be eliminated quickly in rat blood . The results indicated that DBDCT was associated with its rapid clearance from blood, short biological half‐life and relatively serious side effects.…”

Mechanisms by which the antitumor compound di‐n‐butyl‐di‐(4‐chlorobenzohydroxamato)tin(IV) induces apoptosis and the mitochondrial‐mediated signaling pathway in human cancer SGC‐7901 cells

“…In the present study, we investigated the mechanisms by which DBDCT induce apoptosis in SGC‐7901 cells. DBDCT has been shown to have high in vivo antitumor activities, which have been reported to be identical to, or even higher than that of cisplatin 36, 37, and has been shown to induce the apoptosis of human SGC‐7901 cells. Our results show that DBDCT inhibited the growth of SGC‐7901 cells, caused apoptotic DNA fragmentation, blocked cell‐cycle progression in G 1 and/or G 2 –M, and induced apoptosis.…”