Altered pharmacokinetics in the mechanism of chemosensitization: effects of nitroimidazoles and other chemical modifiers on the pharmacokinetics, antitumour activity and acute toxicity of selected nitrogen mustards.

We have studied the effect of misonidazole (MISO) on the antitumour activity, normal tissue toxicity and pharmacokinetics of four bifunctional nitrogen mustards: chlorambucil (CHL); phenylacetic acid mustard (PAAM), a metabolite of CHL; beta, beta-difluorochlorambucil (beta-F2CHL), an analogue which is metabolized less efficiently by the beta-oxidation pathway; and melphalan (MEL). MISO (2.5 mmol/kg) increased the response of the KHT tumour to CHL, PAAM and beta-F2CHL by dose-modifying factors (DMFs) of 1.55-1.85, 1.35-1.65 and 1.5-1.8, respectively. In contrast, the activity of MEL was not altered. However, with 5.0 mmol/kg MISO an enhanced response to MEL was observed (DMF = 1.35-1.55). Similarly, for CHL and PAAM, but not MEL, acute toxicity was also increased by 2.5 mmol/kg MISO. The increase in toxicity with CHL and PAAM was similar to the increase in antitumour activity, and their therapeutic indices were unchanged. Effective chemosensitizers were shown to be powerful inhibitors of drug clearance. Thus, potent chemosensitizers such as MISO, the lipophilic analogue benznidazole (BENZO), the microsomal enzyme inhibitor SKF 525A, and the parent heterocycle imidazole all reduced the plasma clearance of CHL and its metabolites and therefore increased drug exposure (AUC). Conversely, the hydrophilic MISO metabolite Ro 05-9963 was a poor chemosensitizer and produced only very weak pharmacokinetic effects. As the DMFs for chemosensitization agreed very well with those for increased AUC, it seems likely that pharmacokinetic changes are the major cause of the enhancement of tumour response to CHL. For MEL, chemosensitization also appears to be related to pharmacokinetic changes. MISO at a dose of 2.5 mmol/kg produced no change in MEL pharmacokinetics and no enhancement of tumour response, whereas 5.0 mmol/kg MISO was effective on both counts.