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NK611 is a novel water-soluble podophyllotoxin derivative that has comparable antitumour activity but higher potency and better bioavailability in animals as compared with etoposide. The primary objectives of this study were to determine, after both oral and intravenous administration in the same patient, the bioavailability and the pharmacokinetic profile of NK611. Secondary objectives involved evaluation of the toxicity and the antitumor activity. Patients were randomly assigned to receive oral or intravenous (30-min infusion) doses of 5, 10, and 20 mg/m2 on day 1, when pharmacokinetic studies were performed. A daily oral dose of 20 mg/m2 was then given from day 4 through day 7 for respective total doses of 85, 90, and 100 mg/m2. NK611 and its metabolites were determined in plasma and urine by two different high-performance liquid chromatography (HPLC) methods with UV detection. A total of 21 adult patients entered the study and received the complete first cycle and at least the 1st day of cycle 2; 17 of them received at least 2 complete cycles of treatment. After intravenous administration, the plasma decay curve of NK611 followed a two-exponential model, and after oral administration it declined monoexponentially in most cases. At all dose levels, bioavailability values were around 100%. At concentrations between 10 and 20 mg/m2 after both routes of administration, the pharmacokinetics were nonlinear; the terminal half-life, plasma clearance, and volume of distribution were significantly different; and the area under the plasma concentration-time curve was not correlated to the dose. The urinary excretion of NK611 corresponded to 10-15% of the dose after administration by both routes, whereas that of N-demethyl NK611 and its picroform was highly variable. The features of neutropenia were comparable with those noted for etoposide involving a high degree of interpatient variability and recovery within 1 month after treatment. A daily dose of 20 mg/m2 for 5 consecutive days every 4 weeks is the recommended regimen for phase II studies in patients who have never been treated or have undergone previous chemotherapy only once. [ABSTRACT FROM AUTHOR]

SDZ PSC 833 (PSC 833) is a cyclosporin A analogue that is under clinical investigation in combination with doxorubicin (Dx) or other anticancer agents as a type-1 multidrug resistance (MDR-1)-reversing agent. The present study was focused on the effects of PSC 833 on the distribution and toxicity of Dx in non-tumor-bearing CDF1 male mice. Mice were given PSC 833 i.p. at 30 min before i.v. Dx treatment. Dx levels were determined by a high-performance liquid chromatography (HPLC) assay at different times during a 72-h period following Dx treatment in the serum, heart, intestine, liver, kidney, and adrenals of mice. In all tissues, Dx area under the concentration-time curve (AUC) values were much greater in mice receiving 10 mg/kg Dx in combination with 12.5 or 25 mg/kg PSC 833 than in mice receiving Dx alone. The highest increase in Dx concentrations was found in the intestine, liver, kidney, and adrenals. Lower, albeit significant, differences were found in the heart. PSC 833 did not appear to influence either urinary or fecal Dx elimination or Dx metabolism to a great extent. Doses of PSC 833 devoid of any toxicity potentiated the acute and delayed toxicity of Dx dramatically. The mechanism responsible for this enhanced toxicity has not yet been elucidated but is likely to be related to an increased tissue retention of Dx due to inhibition of the P-glycoprotein (Pgp) pump by PSC 833, as has recently been proposed for cyclosporin A. [ABSTRACT FROM AUTHOR]