Influence of hydralazine on the pharmacokinetics of tauromustine (TCNU) in mice

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Abstract
Several investigators including ourselves have shown that hydralazine can potentiate the anti-tumour activity of certain agents against murine tumours probably by manipulating tumour blood flow. In order to investigate the effects of administration of hydralazine on systemic and tumour drug concentrations, we have examined the plasma and tissue pharmacokinetics of the recently developed nitrosourea, Tauromustine (TCNU). The effect of hydralazine on glomerular filtration rate (GFR) in mice was also examined using inulin single injection plasma clearance. An active dose of TCNU (30 mg kg-1) was administered intravenously into non-tumour bearing NMRI mice or mice bearing MAC 15A or MAC 26 subcutaneous tumours. Plasma and tissue levels of TCNU were measured by HPLC. Hydralazine significantly increased (P less than .005 in all cases) the AUCs and decreased the plasma clearance of the drug. Inulin plasma clearance was decreased from 0.258 +/- 0.046 ml min-1 to 0.096 +/- 0.017 ml min-1 (a factor of 2.69) after administration of hydralazine. This decrease in GFR would explain the increased plasma half-lives of a renally cleared drug. It is likely that the increased AUC values are partly responsible for the improved anti-tumour activity of TCNU when administered with hydralazine, but the impact of these findings on toxicity needs to be established.