H2-antagonists and carmustine.
The highly metabolized nitrosourea carmustine (BCNU) is an anticancer agent which alkylates DNA and is metabolized to both active and inactive species by cytochrome P-450 enzymes. Other highly metabolized anticancer drugs have altered toxicities when some histamine H2 antagonists are coadministered. To test this hypothesis with BCNU, DBA/2J male mice were given a single injection of cimetidine (CMT 100 mg/kg) or ranitidine (RNT 25 mg) at various times up to 30 min before, or up to 60 min after a BCNU injection. Spleen colony assays for normal bone marrow stem cell viability showed enhanced toxicity for BCNU when CMT was administered concomitantly. In P-388 leukemia-bearing DBA/2J mice, both CMT and RNT significantly enhanced the antitumor effects of BCNU doses of 30 mg/kg. Pharmacokinetic analyses of BCNU elimination in Cd-1 mice showed marked prolongation of BCNU elimination and increased (BCNU concentration) x time products when CMT was concomitantly administered. These results demonstrate that enhanced BCNU bone marrow toxicity and antitumor activity is produced by CMT. The effect appears to be related to impaired drug clearance when the two agents are administered concurrently. RNT slightly enhanced BCNU antileukemic effects, but it did not significantly alter BCNU myelotoxicity nor drug elimination patterns.
Dorr
R T
RT
Arizona Cancer Center, University of Arizona, Department of Internal Medicine and Pharmacology/Toxicology, Tucson.
Soble
M J
MJ
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects*; D002330:Carmustine / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D002927:Cimetidine / Q000008:administration & dosage; D004357:Drug Synergism; D006635:Histamine H2 Antagonists / Q000008:administration & dosage*; D007941:Leukemia P388 / Q000188:drug therapy*; D007942:Leukemia, Experimental / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D011899:Ranitidine / Q000008:administration & dosage
D006635:Histamine H2 Antagonists; D002927:Cimetidine; D011899:Ranitidine; D002330:Carmustine