Comparative pharmacokinetic and cytotoxic analysis of three different formulations of mitoxantrone in mice

Abstract

MTO, 6.1 imol kg-' for PA-MTO and 4.5 Imol kg-' for pH-MTO. The concentrations of MTO were determined using high-performance liquid chromatography (HPLC) in blood, liver, heart, spleen and kidneys of the mice. Additionally, the toxicity and anti-tumour activity of MTO was evaluated in a xenograft model using a human LXFL 529/6 large-cell lung carcinoma. The dose administered was 90% of the maximum tolerated dose (MTD) of the corresponding formulation (8.1 Amol kg-' for free MTO, 12.1 iimol kg-' for PA-MTO and pH-MTO). The pharmacokinetic behaviour of PA-MTO in blood was faster than that of free MTO, but the cytotoxic effect was improved. In contrast, pH-MTO showed a tenfold increased area under the curve (AUC) in blood compared with free MTO, without improvement of the cytotoxic effect. This discrepancy between the pharmacokinetic and cytotoxic results could be explained by the fact that MTO in pH-MTO liposomes remains mainly in the vascular space, whereas MTO in PA-MTO liposomes is rapidly distributed into deep compartments, even more so than free MTO.

Ultrasound-triggered disruption and self-healing of reversibly cross-linked hydrogels for drug delivery and enhanced chemotherapy

“…A drug dosage of 85 μg per animal was chosen because it yields a systemic dose of ∼3.1 mg/kg, within the dosage range previously shown to reduce xenograft tumor burden in nude mice treated i.v. with mitoxantrone (22,32). Ultrasound treatments were applied for 2.5 min/d with a Sonics VibraCell VCX130 sonicator (2.5 min/d, 13-mm-diameter horn, 120 mW/cm 2 ) once every 24 h. As in the initial in vivo release studies, the ultrasound transducer was coupled to the injected hydrogel by using a thick layer of Aquasonic 100 Medical Ultrasound Transmission Gel applied to the skin of the mice.…”

Plasma membrane targeting by short chain sphingolipids inserted in liposomes improves anti-tumor activity of mitoxantrone in an orthotopic breast carcinoma xenograft model

“…In contrast to free MTO, which could not be detected at the chosen time points due to very short half-life [39][40][41], liposomal formulations strongly improved MTO circulation half-life and thus lowered apparent V ss . Decrease of drug toxicity for liposomal MTO likely reflects these changes in MTO pharmacokinetics and distribution.…”

Effects of Single and Multiple Flavonoids on BCRP-Mediated Accumulation, Cytotoxicity and Transport of Mitoxantrone In Vitro

“…Mitoxantrone also has activity against non-small-cell lung cancer and cancer of the liver, prostate, bladder, and neck (11). Although its structure and activity are similar to the anthracycline derivatives, mitoxantrone has considerably lower cardiotoxicity than doxorubicin (12). Biliary excretion is the major route for elimination of mitoxantrone, and extensive metabolism has not been reported (13).…”