The effect of systemic hyperthermia on melphalan pharmacokinetics in mice

Abstract

Summary The effect of 45min systemic heating at 41°C on plasma and RIF-1 tumour pharmacokinetics of intraperitoneally administered melphalan (MEL) was studied in C3H mice. This heat dose causes greater potentiation of MEL in tumour than in marrow cells, resulting in a therapeutic gain for the combined therapy (Honess & Bleehen, 1985). MEL (7.5mgkg-1) was administered at the start of heating and concentrations assayed from 20-90min by high-performance liquid chromatography (HPLC). With or without heat peak concentrations were achieved by 20 min and were 3 to 4 pg ml -1 in plasma and 1-3 g g-1 in tumour. Higher MEL concentrations in both plasma and tumour were found in heated animals at times after 20 min from injection, but the effect was greater in plasma (2.5-4 fold) than in tumour (1.5-2 fold) where differences were not always significant. At 40 min after a dose of 7.5 mg kg 1, plasma and tumour concentrations in heated animals were equivalent to those after 12.5mgkg-1 and 8.5mgkg-1, respectively, without heating. Tumour/plasma ratios were usually lower in heated than in unheated animals where they often exceeded 100%. The apparent plasma elimination half-life (ti) was 17.5-25min in unheated and 24 44 min in heated animals. The area under the curve (AUC) was increased by a factor of 1.2-1.5 in heated animals, at least partly due to a decrease in volume of distribution. The heat induced increase in MEL exposure may be involved in the enhanced response to the drug, but does not appear to explain the therapeutic gain compaired to MEL alone.We have previously shown that potentiation of melphalan (MEL) by 45min whole body heating at 41°C is greater in two tumours (RIF-1 and KHT) than in normal marrow stem cells (CFUs) in C3H mice (Honess & Bleehen, 1985). This results in a therapeutic gain for the combination of whole body heat with MEL. 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. We have used a paired-ion reversed-phase high-performance liquid chromatography (HPLC) technique to assay MEL in plasma and tumour in unheated and heated mice. Materials and methods MiceFemale C3H/He mice were obtained from Olac (Southern) Ltd, Bicester, UK. Female C3H/Km mice were bred in this unit. Mice were treated at 20-30 g weight. TumourThe RIF-1 tumour described by Twentyman et al. (1980) was grown i.m. in the left hind leg, initiated by an inoculum of 105 cells from culture. Animals were treated wh...

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