Preclinical pharmacology of the anthrapyrazole analog oxantrazole (NSC-349174, Piroxantrone)

Abstract

Oxantrazole (now designated as piroxantrone) is an anthrapyrazole analog under evaluation as a potentially useful anthracycline-like antitumor agent. In preparation for phase I clinical trials, we characterized certain aspects of oxantrazole preclinical pharmacology, including plasma stability, murine pharmacokinetics, in vitro/in vivo metabolism, and DNA damage following incubation with human tumor cells in culture. Oxantrazole was relatively unstable in fresh mouse and dog plasma and particularly unstable in fresh human plasma (t 1/2 less than 5 min at 37 degrees C). Its decomposition in plasma was prevented by the addition of ascorbic acid, suggesting oxidative degradation. Following rapid i.v. administration of oxantrazole to mice, plasma elimination was best described by a two-compartment open model with an elimination-phase half-life, total body clearance, and steady-state volume of distribution of 330 min, 458 ml/min per m2, and 87.9 l/m2, respectively. The c x t value calculated following i.v. administration of 90 mg/m2 oxantrazole to mice was 177 micrograms-min/ml. This value was subsequently used in a pharmacologically guided dose-escalation scheme for the oxantrazole phase I clinical trial. Oxantrazole was converted to a polar conjugate, presumably a beta-glucuronide, by rat but not mouse hepatic microsomal preparations and in vivo by the mouse. Oxantrazole introduced protein-associated DNA strand breaks following incubation with a human rhabdomyosarcoma cell line. Repair of the damage was complete by 15 h. Clinical pharmacologic studies are currently under way in conjunction with the phase I clinical trial of oxantrazole.

Metabolism of (+)-1,4-Dihydro-7-(trans-3-methoxy-4-methylamino-1-pyrrolidinyl)-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic Acid (Voreloxin; Formerly SNS-595), a Novel Replication-Dependent DNA-Damaging Agent

“…Nevertheless, several lines of evidence support identification of metabolite M1 as the acyl glucuronide of voreloxin: 1) acyl glucuronidation is commonly described for carboxylic acid-containing drugs, including fluoroquinolone antibiotics (Dalvie et al, 1996;Ramji et al, 2001;Tachibana et al, 2005), which are structurally related to voreloxin; 2) a glucuronide isolated from rat bile was relatively labile and completely converted to voreloxin under acidic and basic conditions and after incubation with ␤-glucuronidase; 3) the presence of multiple peaks for M1 in bile and not in urine suggests possible intra-acyl rearrangement of the acyl glucuronide in a pH-dependent manner. Intramolecular rearrangement of acyl glucuronides occurs more readily under the alkaline conditions of bile (Hyneck et al, 1988;Frank et al, 1989).…”