Effects of local hyperthermia on the pharmacokinetics of misonidazole in the anaesthetized mouse

Abstract

Summary.-The effects of sodium pentobarbitone anaesthesia, the presence of a tumour, and local hyperthermia to a tumour-bearing leg, on the pharmacokinetics of MISO in the mouse are reported. Analysis of MISO and its metabolite Ro 05-9963 was by high-performance liquid chromatography. The plasma kinetics of MISO were largely unaffected by any of these treatments, but hyperthermia substantially reduced tumour concentrations of the drug.The effects of tumour site and size on unheated-tumour drug concentrations were also studied, and an increase in tumour size was shown to decrease tumour MISO levels, but to different degrees according to whether implanted in the leg or flank.Uniformity of MISO distribution throughout heated and unheated tumours was examined, and levels were found to be constant within tumours. The presence of a temperature detector in heated tumours did not affect their drug concentration.

Effects of localised tumour hyperthermia on pimonidazole (Ro 03-8799) pharmacokinetics in mice

“…Tumour/plasma ratios were also significantly lower in locally heated tumours with a 41% decrease in the average steady-state ratio. This finding is similar to that reported for MISO and LTH (44°Cx60min; Honess et al, 1980) where nitroimidazole concentrations in heated tumours were reduced by up to 70% giving a 25% lower and a reduction of up to 65% in heated tumour/plasma ratios compared to controls. Decreased tumour/plasma ratios in heated tumours may be the result of several factors.…”

“…This finding is in marked contrast to WBH where pimonidazole Noxidation was greatly elevated in mouse plasma during and after the heating period (Walton et al, 1987a). Previous studies with MISO have shown that LTH decreases peak plasma concentrations of the 0-demethylated metabolite of misonidazole, though the metabolite AUCs were comparable in heated and control mice (Honess et al, 1980). In summary, LTH did not alter the acute lethality of pimonidazole in mice.…”

The effect of systemic hyperthermia on melphalan pharmacokinetics in mice

“…(Alberts et al, 1980) and nitrogen mustard in rabbits (Shingleton, 1962). Reduced concentrations in mouse tumours have been reported for misonidazole (Honess et al, 1980) and cyclophosphamide and thiotepa (Longo et al, 1983), also under conditions of drug potentiation. Osieka et al (1978) found no difference in methyl-CCNU uptake in human colon xenografts in nude mice.…”

“…In contrast, under the same conditions, no gain was found for the combination with 3 other alkylating agents, (chlorambucil, cisplatinum and cyclophosphamide), or the nitrosoureas BCNU and CCNU (Honess & Bleehen, 1982, 1985. One of the possible mechanisms may be alteration of drug pharmacokinetics by heat, a topic on which few studies have been carried out (Mimnaugh et al, 1978;Honess et al, 1980;Magin et al, 1980). We have therefore studied the effect of systemic heat at 41°C on the pharmacokinetrics of MEL in plasma and in the RIF-1 tumour in order to investigate whether any heat induced changes in pharmacokinetics would account for the greater heat potentiation in tumour.…”

Radioresistance of the Tumor and Its Solutions (Literature Review)

“…В дальнейшем, основываясь на эксперименталь-ных данных [24,[45][46][47] по усилению радиопоражае-мости опухоли в условиях совместного применения локальной сверхвысокочастотной (СВЧ) гипертермии и МЗ, А. И. Кожушковым [48] проведено клиническое изучение совместного применения МЗ и локальной СВЧ-гипертермии при ЛТ местно-распространенного рака прямой кишки. Обоснованием совместного при-менения 2 радиомодификаторов послужили данные об усилении процессов радиочувствительности и ги-бели гипоксических клеток опухоли в процессе ЛТ [38].…”