title: Comparison of the blood-brain barrier and liver penetration of acridine antitumor drugs.
abstract: The blood-brain barrier penetration of amsacrine and its analogs 9-([2-methoxy-4-[(methylsulfonyl)-amino]phenyl]amino)-,5-dimethyl- 4-acridine carboxamide (CI-921) and M-[2-(dimethylamino)ethyl]-acridine-4-carboxamide (AC) was measured in the barbiturate-anesthetized mouse. After intracarotid administration, AC was almost completely extracted (90%) in a single transit through the brain capillaries, whereas CI-921 (20%) and amsacrine (15%) were moderately extracted. AC is retained in the brain; no loss of AC from the brain was apparent at 1, 2, 4, or 8 min after injection. In contrast, after intraportal administration, 75% of the AC, 94% of the CI-921, and 57% of the amsacrine was extracted in a single transit through the hepatic vasculature. Rather than being retained in the mouse liver, these acridine antitumor agents show time-dependent loss (t1/2 = 10 min for amsacrine and AC, 24 min for CI-921). We conclude that unlike most antitumor agents, these acridine drugs appear to penetrate the blood-brain barrier readily.
authors.affiliation: Southwestern Regional V. A. Epilepsy Center, Veterans Administration West Los Angeles Medical Center, CA 90073.
authors.forename: E M
authors.initials: EM
authors.lastname: Cornford
authors.forename: D
authors.initials: D
authors.lastname: Young
authors.forename: J W
authors.initials: JW
authors.lastname: Paxton
mesh_terms: D000166:Acridines / Q000493:pharmacokinetics*; D000609:Aminoacridines / Q000493:pharmacokinetics; D000677:Amsacrine / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D000758:Anesthesia; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics; D001463:Barbiturates; D001812:Blood-Brain Barrier / Q000502:physiology*; D001921:Brain / Q000098:blood supply / Q000378:metabolism; D000440:Butanols / Q000493:pharmacokinetics; D002339:Carotid Arteries; D003975:Diazepam / Q000493:pharmacokinetics; D007269:Injections, Intra-Arterial; D007275:Injections, Intravenous; D008099:Liver / Q000378:metabolism*; D051379:Mice; D011169:Portal Vein
chemical_list: D000166:Acridines; D000609:Aminoacridines; D000970:Antineoplastic Agents; D001463:Barbiturates; D000440:Butanols; D000677:Amsacrine; C058332:N-(2'-(dimethylamino)ethyl)acridine-4-carboxamide; D003975:Diazepam; C042315:asulacrine