Pharmacokinetics Of (+)-1,2-Di(3,5-Dioxopiperazin-1-Yl)Propane Intravenous Infusions In Adult Cancer Patients

Robert H. Earhart, Kendra D. Tutsch, Jim M. Koeller, Rey Rodriguez, H. Ian Robins, Douglass C. Tormey, Hugh L. Davis, Charles L. Vogel

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    32 Scopus citations

    Abstract

    (+)-1,2-Di(3,5-dioxopiperazin-1-yl)propane (ICRF-187), the D-enantiomer of the racemic antitumor agent (±)-1,2-di(3,5-dioxopiperazin-1-yl)propane, displays schedule-dependent toxicity in humans and animals. Pharmacokinetic factors which might produce schedule-dependent toxicity were studied in patients during a Phase I trial. The intact drug was assayed by high-performance liquid chromatography in simple aqueous solutions by direct injection or in urine, bile, pleural fluid, or serum after extraction and concentration. Ultraviolet absorbance was monitored at 208 nm. ICRF-187 and an internal standard of ICRF-192 were eluted as separate peaks. Peak height and peak area ratios of ICRF-187 to ICRF-192 were linear over serum ICRF-187 concentrations from 0.05 to 100 µg/ml. The detection limit for ICRF-187 was 2 ng by direct injection, and the quantitation limit in serum was 0.05 µg/ml. Using equilibrium dialysis, there was no evidence for significant protein binding of ICRF-187. Urine and serum specimens were collected during and following i.v. infusions of 1.0 g/sq m ICRF-187 by three different schedules (30-min, 8-hr, and 48-hr infusions) to five adult patients. Total urinary drug recovery was schedule independent, averaging 48%. Serum drug kinetics followed a two-compartment open model (r2 > 0.98 for all infusions). Mean peak serum levels for the three schedules were 75.3, 22.8, and 2.9 αg/ml, respectively. Mean central compartment volume of distribution was 0.193 liter/kg, or slightly greater than the expected inulin space. Mean f1/2α values were not significantly different among the schedules (9.9, 10.6, and 19.5 min, respectively), nor were mean f1/2 β values (121.4, 143.6, and 173.0 min, respectively). Integrals of the concentration-time curves did not differ with schedule. Intact ICRF-187 distributed into pleural effusions and was cleared at rates reflecting rapid equilibration with serum in one patient and slower equilibration in a second patient. Biliary drug concentration equaled serum drug concentration in the terminal phase in one patient. Infusion of ICRF-187 over periods >8 hr was necessary for achievement of true steady-state conditions. The greater biological effect of prolonged infusions is probably based upon drug action rather than upon pharmacokinetic factors and thus might be associated with improved antitumor activity.

    Original languageEnglish (US)
    Pages (from-to)5255-5261
    Number of pages7
    JournalCancer Research
    Volume42
    Issue number12
    StatePublished - Dec 1 1982

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

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