Interaction of Cimetidine but not Ranitidine with Cyclophosphamide in Mice1

A series of experiments in DBA/2J mice evaluated the biological and pharmacokinetic interactions of the alkylating agent Cyclophosphamide (CIA)and the histamine-H; antagonistscimetidine(CMT)and ranitidine (RNT). Doses were adjusted to approximate human dose levels: 100 mg/ kg for CMT; and 25 mg/kg for RNT. CMT reduced the survival of normal (bone marrow stem cell) colony forming units in a dose dependent fashion. CMT, given 5 or 30 min before CIA (200 mg/kg), significantly increased the survival of leukemia bearing mice, as well as the elimination half-life and plasma area under the curve of total alkylating metabolites of CIA. RNT did not significantly alter CIA antileukemic activity, pharmacokinetics, or toxicity to normal bone marrow stem cells. These results suggest caution in the use of CMT in patients being treated with CTX in order to avoid the possibility of exaggerated CIV toxicities. RNT may comprise a safer histamine-Hi antagonist to use with CTX if a histamine-H2 antagonist is clinically indicated.