Chemosensitization of the nitrosoureas by 2-nitroimidazoles in the subcutaneous 9L tumor model: pharmacokinetic and structure-activity considerations.

Alterations of the pharmacokinetics and cytotoxic effects of the nitrosoureas, 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and 1-(2-chloroethyl)-3-(cyclohexyl)-1-nitrosourea (CCNU) by the 2-nitroimidazoles, misonidazole (MISO) and SR-2508 were investigated using the subcutaneous (sc) 9L tumor model in male Fisher 344 rats. When 50 mg/kg of CCNU was given i.p., the peak plasma concentration of CCNU was about 3 micrograms/ml. CCNU was eliminated with biphasic kinetics that had a terminal half-time (T1/2) of approximately 47 min. When 2.5 mmole/kg of MISO was given i.p. 150 min before CCNU, the peak plasma concentration of CCNU was increased by approximately 63% with no change in the elimination kinetics. Clamping did not change the pharmacokinetics of CCNU in either plasma or tumors. MISO pretreatment increased the peak CCNU concentration in unclamped tumors by 3-fold, but had no effect on the CCNU pharmacokinetics in clamped tumors. With the exception of a decrease in the peak BCNU concentration in tumors similar to that observed with MISO, SR-2508 (3.75 mmole/kg, i.p.) did not change the pharmacokinetics of BCNU or CCNU in plasma and tumors. CCNU had no effect on the MISO concentration in plasma and unclamped tumors. However, in the clamped tumors, CCNU delayed the return of the MISO concentration to the unclamped tumor level by about an additional 60 min after the clamp was released. SR-2508 was eliminated from the plasma with biphasic kinetics having an initial and terminal T1/2 of approximately 11 and approximately 76 min, respectively. SR-2508 reached a peak tumor concentration of about 500 micrograms/ml in 30 min. The elimination T1/2 for SR-2508 in unclamped and clamped tumors was approximately 81 and approximately 42 min, respectively. When the clamp was released, the SR-2508 concentration returned to the level found in the unclamped tumors approximately 90 min after it reached its nadir; BCNU and CCNU had no effect on the kinetics of this process. MISO significantly potentiated the cytotoxicity of BCNU in clamped tumors at surviving fractions less than or equal to 0.5. MISO did not potentiate the cytotoxicity of CCNU until the surviving fraction reached 0.05. SR-2508 did not potentiate the cytotoxicity of either BCNU or CCNU.(ABSTRACT TRUNCATED AT 400 WORDS)