Pharmacokinetics, metabolism and distribution of 1,2-dihydro-8-(4-methylpiperazinyl)-4-phenylimidazo [1,2-al pyrido [3,2-el pyrazine-5-oxide in C3H mice

Abstract

Purpose: 1,2-Dihydro-8-(4-methylpiperazinyl)-4-phenylimidazo [1,2- a] pyrido [3,2- e] pyrazine-5-oxide (RB90740) is a bioreductive drug with an oxic to hypoxic toxicity ratio of 16 in cultured V79 cells in vitro. The aim of this study was to examine the pharmacokinetics, metabolism and distribution of the drug in tumor bearing C3H mice. Methods and Materials: A high pressure liquid chromatography assay for the quantitative determination of concentrations of the drug and its metabolites has been developed and used to examine their distribution in blood, RIF-1 and KHT tumors, brain, muscle, and liver tissue. Urine and feces collected for 24 h after drug administration have been examined for the drug and its metabolism products. Results: Three metabolites, two of which have been identified, have been observed in mouse tissue. 1,2-Dihydro-8-(4-methylpiperazinyl)-4-phenylimidazo [1,2- a]pyrido[3,2- e]pyrazine (RB92815) is the two-electron reduced species, which is observed in liver, urine and occassionally in tumor samples. 1,2-dihydro-8-(4-piperazinyl)-4-phenylimidazo [1,2- a]pyrido[3,2-elpyrazine-5-oxide (11131739), the N-demethylated compound, is observed in urine and liver. Elimination of the drug after an intraperitoneal dose of 50 mg/kg is biphasic with t 12 α = 3 min and t 12 β = 219 min. The area under the curve for blood concentration vs. time is 1.4 mg ml min −1. The drug is preferentially taken up into tumor tissue as is apparent from the area under the curve values for RIF-1 (28.3 mg ml min −1) and KHT (18.4 mg ml min −1) tumors. Conclusion: From these values of the area under the curve it is suggested that the drug is present in tumor tissue at concentrations sufficient to eliminate the hypoxic fraction provided reduction to a toxic species occurs. Bioreduction by the addition of two electrons to form RB92815 occurs in some tumors, but it is not known if this is due to an obligate two-electron detoxifying step or if reduction occurs by single electron additions via a toxic free radical species.