Biochemical pharmacology and toxicology of formycin alone and in combination with 2'-deoxycoformycin (pentostatin).
The toxicology and pharmacology of formycin both as a single agent and combined with the adenosine deaminase inhibitor 2'-deoxycoformycin (dCF) were examined in outbred Swiss mice heterozygous for the nude gene (nu/+). The LD10 for formycin alone given on a daily x 5 schedule was 21 mg/kg. When the animals were pretreated with 1 mg/kg of dCF 1 hour prior to each dose of formycin, toxicity was approximately doubled, ie, LD10 was reduced to 10 mg/kg. Death was associated with hepatic toxicity in both treatment regimens; suppression of leukocyte counts was mild except at doses greater than the LD10. Formycin nucleotides were detected by high-performance liquid chromatography in the livers of mice treated with formycin either alone or combined with dCF. When isolated rat hepatocytes were incubated for 2 hours with either formycin or dCF plus formycin, analog nucleotides accumulated in the cells. Cellular ATP decreased to below the limits of detection, whereas a large peak corresponding to formycin-5'-triphosphate was present. This replacement of cellular ATP by formycin-5'-triphosphate may help explain the hepatic toxicity observed.
D058892:Adenosine Deaminase Inhibitors; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D001219:Aspartate Aminotransferases / Q000097:blood; D001663:Bilirubin / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D001806:Blood Urea Nitrogen; D003070:Coformycin / Q000031:analogs & derivatives / Q000494:pharmacology / Q000633:toxicity*; D003401:Creatine / Q000097:blood; D004357:Drug Synergism; D005260:Female; D005573:Formycins / Q000494:pharmacology / Q000633:toxicity*; D007928:Lethal Dose 50; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008819:Mice, Nude; D015649:Pentostatin; D051381:Rats; D012263:Ribonucleosides / Q000633:toxicity*
D058892:Adenosine Deaminase Inhibitors; D000903:Antibiotics, Antineoplastic; D001786:Blood Glucose; D005573:Formycins; D012263:Ribonucleosides; D003070:Coformycin; D015649:Pentostatin; C034550:formycin; D001219:Aspartate Aminotransferases; D003401:Creatine; D001663:Bilirubin