Pharmacokinetics and tissue distribution of novel platinum containing anticancer agent BP‐C1 studied in rabbits using sector field inductively coupled plasma mass spectrometry

Abstract

A method of platinum quantification in whole blood samples after microwave digestion using sector field inductively coupled plasma mass spectrometry has been developed. The following analytical figures of merit have been established: limit of detection 1.1 µg/L for blood samples, dynamic range 3.6–200 µg/L, intra‐day precision (relative standard deviation, n = 9) did not exceed 5%. Spiked samples were analyzed for method validation. The method was used for pharmacokinetics studies of a novel anti‐cancer drug BP‐С1, a complex of cis‐configured platinum and benzene‐poly‐carboxylic acids. Main pharmacokinetic parameters (area under curve, maximum concentration, clearance, half‐life times for α‐ and β‐phase) were estimated for two dosage forms of BP‐C1 0.05 and 0.125 mass %. Pharmacokinetic curves were assessed for single and course administration. Studies were performed using rabbits (n = 6) as a model. BP‐C1 was injected intramuscularly. The study established dose proportionality of the tested dosage forms and suggested clinical dosing schedule: 5 days of injections followed by 2 days’ break. Platinum tissue distribution was studied in tissue samples collected 20 days after the last injection. Predominant platinum accumulation was observed in kidneys, liver, and muscles near injection site. ‘Slow’ phase of platinum excretion kinetics may be related to the muscles at the injection site. © 2015 The Authors. Drug Testing and Analysis published by John Wiley & Sons Ltd.

Preclinical Pharmacokinetics and Biodistribution of Anticancer Dinuclear Palladium(II)-Spermine Complex (Pd2Spm) in Mice

“…In turn, a 74.2% higher accumulation of Pd (from Pd 2 Spm) relative to Pt (from cisplatin) was determined in the kidney. This very large disparity in the accumulation of Pd and Pt in the kidney compared to the other organs was an expected outcome, which agrees with previous reports for several Pt-based compounds [ 39 , 40 , 41 ]. The dose-dependent nephrotoxicity of Pt-based drugs results from the binding of the drug´s Pt center to thiol-containing renal enzymes (e.g., metallothioneins) [ 24 ] but, as shown for oxaliplatin and carboplatin, which displayed a higher and lower renal accumulation than cisplatin, respectively [ 42 ], the total content of Pt accumulated in the kidney is an unreliable biomarker of nephrotoxicity, and attention should be paid to specific interactions between the drug/its metabolites and renal biomolecules likely to be responsible for functional deviation and associated toxicity [ 36 , 42 , 43 ].…”

Modeling of Chemoperfusion vs. Intravenous Administration of Cisplatin in Wistar Rats: Adsorption and Tissue Distribution

“…For platinum quantification, inductively coupled plasma mass spectrometry (ICP-MS) was used as described previously [ 47 , 48 ]. In brief, a microwave system UltraClave™ (Milestone, Sorisole, Italy) was used for sample digestion.…”

“…An Analytik Jena PlasmaQuant MS Elite (Analytik Jena, Jena, Germany) mass spectrometer with a quartz concentric Micromist nebulizer, +3 °C Peltier-cooled glass spray chamber, and standard nickel cones was used. The following instrument parameters were used: collision mode, helium flow 120 mL/min; plasma parameters: plasma gas flow 9 L/min, auxiliary gas flow 1.35 L/min, nebulizer gas flow 1.08 L/min (daily optimized), plasma RF power 1360 W. The result was calculated as a mean of 9 replicate measurements of the corresponding mass to charge ratio (195 for Pt and 89 for Y, internal standard) unless relative standard deviation (RSD) exceeded 5% [ 47 ]. Internal calibration was plotted in the range 1.0–10.0 µg/L.…”

“…The calibration was established directly before analyzing the samples and its stability was controlled after every 10 samples. The procedure was previously validated using the spiking method in the range 4.1 µg/L (limit of quantification) to 200 µg/L [ 47 ]. Additionally, quality controls samples with known concentration of platinum were randomly distributed between the samples under study and analyzed blindly to ensure data quality.…”

Lipid-chitosan hybrid nanoparticles for controlled delivery of cisplatin

“…Blood samples were collected at defined time intervals over a period of 24 hours and centrifuged immediately to separate plasma. The plasma samples were treated with nitric acid: perchloric acid to remove plasma proteins (Navolotskii et al., 2015). Plasma was stored at –20 °C.…”