PHARMACOKINETICS, CEREBROSPINAL-FLUID PENETRATION, AND METABOLISM OF PIROXANTRONE IN THE RHESUS-MONKEY

Piroxantrone is an anthrapyrazole derivative with broad anti-tumor act ivity in vitro and less cardiac toxicity than the anthracyclines. The metabolic pathways and central nervous system penetration of piroxantr one have not been determined. In this study we examined the pharmacoki netic behavior of piroxantrone in plasma and cerebrospinal fluid in a non-human primate model. In addition, a urinary metabolite of piroxant rone was isolated and its cytotoxicity evaluated in vitro. The disappe arance of piroxantrone from plasma after an intravenous dose of 150 mg /m(2) given over 60 minutes was biexponential with mean t(1/2) alpha o f 1.0 minutes and a mean t(1/2) beta of 180 minutes. The mean area und er the curve was 220 mu M min and the clearance was 1420 ml/min/m(2). Piroxantrone was not detectable in the cerebrospinal fluid. Piroxantro ne and three other compounds not present in pre-treatment samples were detected in urine. The major urinary metabolite was isolated. Its cyt otoxicity against MOLT-4 cells in vitro was at least one log less than that of piroxantrone. In addition, one of the other compounds detecte d in urine was determined to be a glucuronide conjugation product of t he major metabolite. The results of this study may be useful in the in terpretation of the activity and toxicity of piroxantrone in clinical trials.