Abstract
We have investigated the effect of misonidazole (MISO) on the pharmacokinetics of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) in mice. CCNU and its monohydroxylated metabolites were measured using a high performance liquid chromatography (HPLC) method. In the absence of MISO the plasma disappearance of CCNU was biphasic with a t 1/2 alpha of 2.3 min and a t 1/2 beta of 53 min. The monohydroxylated metabolites of CCNU also followed biphasic clearance kinetics. A large single dose of MISO (0.5 mg g-1), given i.p. 30 min prior to CCNU, prolonged the t 1/2 alpha by a factor of 2.6 but had no effect on t 1/2 beta. In addition, the apparent volume of distribution was decreased by a factor of 1.6. Consequently, the plasma area under the curve (AUC0 - infinity) was increased by a factor of 1.7 for CCNU and by a factor of 2.0 for total nitrosourea (CCNU + monohydroxylated metabolites). The effects of MISO on CCNU kinetics were dependent on MISO dose and plasma concentration and on the interval between MISO and CCNU administration. The concentration of CCNU was measured in 4 tumours: the KHT, RIF-1 and EMT6 mouse tumours, and the HT29 xenograft. For all 4 tumours, 0.5 mg g-1 MISO raised the tumour concentrations of CCNU and total nitrosourea by a considerable amount (2-2.5 times). More detailed studies in the KHT tumour demonstrated that there was a significant lag period before peak tumour CCNU concentrations were reached, and that MISO increased the peak concentrations by a factor of about 2.4. In contrast, there was no such lag period for the plasma and MISO did not increase the plasma peak CCNU concentrations. These data strongly suggest that modification of the pharmacokinetics may be a major contributory factor in the enhancement of CCNU cytotoxicity by large single doses of MISO in vivo.
Highlights
KHT and RIF-1 tumours were grown in C3H mice, EMT6 tumours in BALB/c mice and HT29 xenografts in CBA nude t The Macmillan Press Ltd., 1983
Montgomery et aL (1976) using a very similar high performance liquid chromatography (HPLC) system reported that the elution of the cis-trans pairs of monohydroxylated CCNUs occurs in the order of alternating diequatorial and axial-equatorial
The tumour concentrations of CCNU generally reflect the plasma concentrations, and MISO has the effect of increasing the tumour exposure to the cytotoxic nitrosoureas.*
Summary
MISO was supplied by Roche Products Ltd. and CCNU by the Drug Synthesis and Chemistry Branch of the National Cancer Institute, USA, and by Lundbeck. The synthetic monohydroxylatedCCNU metabolites were kindly given by Dr T.P. Johnston of the Southern Research Institute, Alabama, U.S.A. Mice and tumours. Inbred female C3H/He and male BALB/c mice were supplied by OLAC. Male CBA nude mice were supplied by NIMR (Mill Hill). KHT and RIF-1 tumours were grown in C3H mice, EMT6 tumours in BALB/c mice and HT29 xenografts in CBA nude t The Macmillan Press Ltd., 1983
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