PHARMACOKINETICS OF VARYING DOSES OF NICOTINAMIDE AND TUMOR RADIOSENSITIZATION WITH CARBOGEN AND NICOTINAMIDE - CLINICAL CONSIDERATIONS

Plasma concentrations, after administration of varying doses of nicoti namide, were measured in CBA male mice using a newly-developed high pe rformance liquid chromatography assay. In all dose groups, peak levels were observed within the first 15 min after an i.p. administration of 0.1, 0.2, 0.3 or 0.5 mg g-1 of nicotinamide. There was a clear dose-d ependent increase in plasma concentration with increasing dose, with a lmost a five-fold lower concentration (1.0 vs 4.9 mumol ml-1) achieved with a dose of 0.1 mg g-1 compared with 0.5 mg g-1, respectively. The half-life of nicotinamide increased from 1.4 h to 2.2 h over the dose range (P<0.01). Comparisons with previous pharmacokinetic data in hum ans show that clinically-relevant oral doses of 6 and 9 g in humans gi ve plasma levels slightly higher than those achieved at 1 h with doses of 0.1 to 0.2 mg g-1 in mice. Tumour radiosensitisation with carbogen alone, and with carbogen combined with varying doses of nicotinamide (0.05 to 0.5 mg g-1), was investigated using a 10-fraction in 5 days X -ray schedule. Relative to air-breathing mice, a statistically signifi cant increase in sensitisation was observed with both a local tumour c ontrol and with an in vivo/in vitro excision assay (P less-than-or-equ al-to 0.007). With the local control assay, a trend was observed towar ds lower enhancement ratios (ERs) with decreasing nicotinamide dose (f rom 1.85 to 1.55); carbogen alone was almost as effective as when comb ined with 0.1 mg g-1 of nicotinamide. With the excision assay, ERs for carbogen combined with nicotinamide increased with decreased levels o f cell survival. At a surviving fraction of 0.02, enhancement ratios o f 1.39-1.48 were obtained for carbogen plus 0.1 to 0.3 mg g-1 of nicot inamide. These were lower than those seen with the two higher doses of 0.4 to 0.5 mg g-1 (ERs = 1.63 - 1.69).