Pharmacokinetics, cerebrospinal fluid penetration, and metabolism of piroxantrone in the Rhesus monkey

Piroxantrone is an anthrapyrazole derivative with broad anti-tumor activity in vitro and less cardiac toxicity than the anthracyclines. The metabolic pathways and central nervous system penetration of piroxantrone have not been determined. In this study we examined the pharmacokinetic behavior of piroxantrone in plasma and cerebrospinal fluid in a non-human primate model. In addition, a urinary metabolite of piroxantrone was isolated and its cytotoxicity evaluated in vitro. The disappearance of piroxantrone from plasma after an intravenous dose of 150 mg/m2 given over 60 minutes was biexponential with mean t1/2 alpha of 1.0 minutes and a mean t1/2 beta of 180 minutes. The mean area under the curve was 220 microM.min and the clearance was 1420 ml/min/m2. Piroxantrone was not detectable in the cerebrospinal fluid. Piroxantrone and three other compounds not present in pre-treatment samples were detected in urine. The major urinary metabolite was isolated. Its cytotoxicity against MOLT-4 cells in vitro was at least one log less than that of piroxantrone. In addition, one of the other compounds detected in urine was determined to be a glucuronide conjugation product of the major metabolite. The results of this study may be useful in the interpretation of the activity and toxicity of piroxantrone in clinical trials.