CNS toxicity and CSF pharmacokinetics of intraventricular DFMO and MGBG in beagle dogs.
We have developed a beagle dog model to study the pharmacology and toxicology of anticancer drugs administered through the 3rd or lateral ventricles. A Foltz-type reservoir was implanted SC and connected by tube into a cerebral ventricle. Drugs were administered directly into the reservoir; CSF sampling of drugs administered into the ventricle was achieved directly by tapping the reservoir or by percutaneous puncture of the cisterna magna. In the current study, we evaluated the CSF pharmacokinetics and CNS toxicity of two inhibitors of polyamine metabolism, alpha-difluoromethylornitine (DFMO) and methylglyoxal bisguanylhydrazone (MGBG). Both drugs were judged too toxic to justify intrathecal or intraventricular studies with these agents in patients.
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000134:cerebrospinal fluid*; D002552:Cerebral Ventricles / Q000187:drug effects; D004285:Dogs; D000518:Eflornithine; D006146:Guanidines / Q000633:toxicity*; D007276:Injections, Intraventricular; D008297:Male; D008657:Metabolic Clearance Rate; D008935:Mitoguazone / Q000008:administration & dosage / Q000134:cerebrospinal fluid / Q000633:toxicity*; D009952:Ornithine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000134:cerebrospinal fluid / Q000633:toxicity
D000964:Antimetabolites, Antineoplastic; D006146:Guanidines; D009952:Ornithine; D008935:Mitoguazone; D000518:Eflornithine