The pharmacokinetics of prednimustine and chlorambucil in the rat

Summary

In the rat prednimustine, the prednisolone ester of chlorambucil, is much less toxic than equimolar doses of chlorambucil, when administered subcutaneously (SC). This is due to differences in alkylating agent pharmacokinetics. Prednimustine injected SC produced low plasma concentrations (<5 μM) of the alkylating metabolites chlorambucil and phenyl acetic mustard, which were maintained for 48 h. No unhydrolysed prednimustine could be detected. Chlorambucil, in contrast, was rapidly absorbed, peak levels (40 μM) occurring within 2 h, after which chlorambucil and phenyl acetic mustard plasma levels decreased with half-lives of 2.4 h and 2.9 h respectively.

The toxicity of chlorambucil could be similarly reduced by administering either the methyl ester of clorambucil or by giving chlorambucil in a multiple-treatment low-dose schedule. Neither of these treatments inhibited the Yoshida alkylating agent-resistant tumour, however, whereas prednimustine or a combination of chlorambucil and prednisolone produced significant tumour growth inhibition. Prednisolone did not alter chlorambucil pharmacokinetics. Thus the reduced toxicity of prednimustine is due to chlorambucil esterification and the subsequent alteration in pharmacokinetics, whilst inhibition of alkylating agent-resistant tumours results from the combination of chlorambucil and prednisolone.