PHARMACOKINETICS OF 9-METHOXY-N, N-DIMETHYL-5-NITROPYRAZOLO [3,4,5-KL]ACRIDINE-2(6H)-PROPANAMINE (PZA, PD-115934, NSC-366140) IN MICE - GUIDELINES FOR EARLY CLINICAL-TRIALS

Pharmacokinetic studies that consisted of measuring the plasma drug pr ofile, tissue drug distribution, and elimination in urine and feces we re performed in female C57BL/6 x DBA/2 (hereafter called B6D2F(1)) and male B6D2F(1)A/2 and C57BL/6 x CH3 (hereafter called B6C3F(1)) mice f ollowing treatment with a 1-h i.v. infusion of the PZA, PD115934 (NSC 366140), This drug is the first of a new class of cytotoxic agents and was selected for clinical trials because of both its broad antitumor activity in vivo against murine solid tumors and human xenografts, and its ill vivo toxicity profile that was predictable based on drug dose and schedule of administration, The pharmacokinetic results obtained here in mice have been used to facilitate the dose escalations during the Phase I trial and to determine pharmacokinetic drug exposure targe ts for its acute and subacute toxic effects, Plasma samples from three to four mice per time point were pooled, and then individual tissue s amples from the same mice were collected at specified times following treatment, All samples were prepared using solid-phase extraction and assayed using high pressure liquid chromatography, The acute dose-limi ting toxicity was neurological and occurred immediately after treatmen t at 300 mg/m(2), The peak plasma level range at the acute maximum tol erated dose was 1040-1283 ng/ml, Thus, peak plasma levels < 1000 ng/ml were the acute toxicity target, Variations in the area under the plas ma drug concentration x the time curve were observed that did not appe ar to be related to sex or age, The previously defined subacute dose-l imiting toxicity was myelosuppression that occurred at a maximum toler ated dose of 600 mg/m(2) (300 mg/m(2) x 2) in B6D2F(1) females, Thus, the area under the plasma drug concentration x the time curve in B6D2F (1) females at this dose (1048 mu g/ml x min) was the area under the p lasma drug concentration x the time curve target, Drug levels were det ected at 60 min following treatment in all tissues examined with a pla sma:tissue ratio as high as 1:500, The organs with the highest levels were kidney, pancreas, liver, lung, and brain, Fecal excretion was low (range, 0.04-0.20% of the dose administered) and was not clearly diff erent between males and females, Urinary excretion was higher (range, 5-28% of the dose administered) and did show evidence of sex-related d ifferences, with male urinary drug excretion being higher than female urinary drug excretion, The drug was greater than or equal to 95% prot ein bound, Preliminary evidence for drug metabolism was found in urine and feces and sill be further explored.