Pharmacokinetics and tissue distribution of psammaplin A, a novel anticancer agent, in mice

Abstract

This study reports the pharmacokinetics and tissue distribution of a novel histone deacetylase and DNA methyltransferase inhibitor, psammaplin A (PsA), in mice. PsA concentrations were determined by a validated LC-MS/MS assay method (LLOQ 2 ng/mL). Following intravenous injection at a dose of 10 mg/kg in mice, PsA was rapidly eliminated, with the average half-life (t(1/2, λn)) of 9.9 ± 1.4 min and the systemic clearance (CL(s)) of 925.1 ± 570.1 mL/min. The in vitro stability of PsA was determined in different tissue homogenates. The average degradation t(1/2) of PsA in blood, liver, kidney and lung was found relatively short (≤ 12.8 min). Concerning the in vivo tissue distribution characteristics, PsA was found to be highly distributed to lung tissues, with the lung-to-serum partition coefficients (K(p)) ranging from 49.9 to 60.2. In contrast, PsA concentrations in other tissues were either comparable with or less than serum concentrations. The high and specific lung targeting characteristics indicates that PsA has the potential to be developed as a lung cancer treatment agent.

Profile of disposition, tissue distribution and excretion of the novel anti-human immunodeficiency virus (HIV) agent W-1 in rats

“…The value of V d /F for W-1 was much greater than the total body water of rats (668 mL/kg) (Davies and Morris 1993;Minematsu et al 2012), implying that drug concentration in tissues was higher than plasma. The value of CL/F was 46.56 ± 7.45, 42.55 ± 7.78 and 38.66 ± 4.57 L h -1 kg -1 for 50, 100 and 200 mg/kg, respectively, which suggested that W-1 had a rapid clearance in rats (Kim et al 2012;Chen et al 2015).…”

Determination and validation of psammaplin A and its derivatives in rat plasma by liquid chromatography–tandem mass spectrometry and its application in pharmacokinetic study

“…To achieve optimized LC condition, several kinds of columns were tested in our preliminary study (data not shown) based on studies by Kim et al [30]. Among them, Synergi TM 4 Hydro-RP 80 Å column (75 × 2.0 mm; Phenomenex, CA, USA) provided best peak symmetry, short run time, and decent signal response, thus it was selected in this investigation.…”

“…The best peak shape and shortest retention time of analytes were observed at 0.4 mL/min flow rate. Therefore, compared to the method by Kim et al [30], simultaneous analyses of the three PsA derivatives with improved mobile phase conditions and run time has been achieved. Moreover, in the preliminary study, acetonitrile was used for the precipitation of plasma proteins and this sample pretreatment method provided Table 1 Within-and between-run precision and accuracy for PsA and its derivatives in rat plasma.…”

“…The other major problem of PsA is its poor pharmacokinetic properties. According to the pharmacokinetic study data after intravenous injection at a dose of 10 mg/kg in mice [30], the average half-life and the systemic clearance values of PsA were 9.9 ± 1.4 min and 925.1 ± 570.1 mL/min/kg, respectively, which means its elimination in in vivo condition is so rapid that the build-up of enough therapeutic concentration of PsA in tumor region over a sufficient period of time would be unachievable without any improvement in its pharmacokinetic properties.…”

Marine Sponge Derived Antiangiogenic Compounds

“…Because of their multi(epi)target features and their action in ex vivo samples, psammaplin A and its derivatives are attractive molecules for the modulation of epigenetic disorders [119,120]. Recent pharmacokinetics and tissue distribution studies indicate a preferential distribution of psammaplin A to lung, suggesting the potential of this compound as a lung cancer treatment agent [121].…”