PHARMACOKINETIC CONTRIBUTION TO THE IMPROVED THERAPEUTIC SELECTIVITY OF A NOVEL BROMOETHYLAMINO PRODRUG (RB-6145) OF THE MIXED-FUNCTION HYPOXIC CELL SENSITIZER CYTOTOXIN A-(1-AZIRIDINOMETHYL)-2-NITRO-1H-IMIDAZOLE-1-ETHANOL (RSU-1069)

RB 6145 is a novel hypoxic cell sensitizer and cytotoxin containing both an essential bioreductive nitro group and a bromoethylamino substituent designed to form an alkylating aziridine moiety under physiological conditions. In mice, RB 6145 is 2.5 times less toxic but only slightly less active than the aziridine analogue RSU 1069, giving rise to an improved therapeutic index. However, the mechanism for the enhanced selectivity is not clear. Reasoning that this may lie in a more beneficial pharmacokinetic profile, we investigated the plasma pharmacokinetics, tissue distribution and metabolism of RB 6145 in mice using a specially developed reversed-phase HPLC technique. An i.p. dose of 190 mg kg-1 (0.5 mmol kg-1) RB 6145 produced peak plasma concentrations of about 50-mu-g ml-1 of the pharmacologically active target molecule RSU 1069 as compared with levels of around twice this value that were obtained using an equimolar i.p. dose of RSU 1069 itself. The plasma AUC0- infinity value for administered RSU 1069 was ca. 47-mu-g ml-1 h and that for the analogue RSU 1069 was ca. 84-mu-g ml-1 h. No prodrug was detectable. Another major RB 6145 metabolite in plasma was the corresponding oxazolidinone, apparently formed on interaction of the drug with hydrogen carbonate. The oxazolidinone initially occurred at higher concentrations than did RSU 1069, with the levels becoming very similar from 30 min onwards. Post-peak plasma concentrations of both RB 6145 metabolites declined exponentially, displaying an elimination t1/2 of ca. 25 min, very similar to the 30-min value observed for injected RSU 1069. The plasma AUC0- infinity value for the metabolite RSU 1069 was about 1.3 and 1.6 times higher following i.p. injection of 95 mg kg-1 (0.25 mmol kg-1) of the prodrug as compared with administration via the oral and i.v. routes, respectively. After i.v. injection, peak levels of the oxazolidinone metabolite were twice those observed following both i.p. and oral dosing and possibly contributed to the acute toxicity. After an i.p. dose of 190 mg kg-1 RB 6145, concentrations of RSU 1069 and the oxazolidinone metabolites rose to 40% and 33%, respectively, of the ambient plasma level in i.d. KHT tumours. The peak level of metabolite RSU 1069 was ca. 6-mu-g g-1 as compared with 10-mu-g g-1 following an equimolar dose of RSU 1069 itself; the tumour AUC0- infinity value for the metabolite RSU 1069 was some 35% lower. The AUC0- infinity in brain for RSU 1069 formed from RB 6145 was about 1.8 times lower than that obtained using an equimolar dose of the analogue RSU 1069. The hydrophilic oxazolidinone metabolite of RB 6145 showed tumour penetration similar to that of the metabolite RSU 1069 but was substantially excluded from brain tissue. About 34% of the delivered dose of RB 6145 appeared in the urine as the oxazolidinone and 12% as RSU 1069. We feel that the improved antitumour specificity observed for RB 6145 as compared with RSU 1069 may be explained at least in part by the more favourable tissue disposition of the metabolites, particularly the similar uptake of both the RSU 1069 metabolite and the oxazolidinone by tumour tissue, coupled with the lower brain exposure following prodrug administration.