Arterial drug infusion with extracorporeal removal. II. Internal carotid carmustine in the rhesus monkey.
During cancer chemotherapy by intra-arterial drug administration, systemic toxicity often limits the tolerable dose. We evaluated the pharmacokinetic advantage obtained by infusing carmustine (BCNU) into the internal carotid artery during BCNU removal from the blood from the perfused region by hemoperfusion. A hemoperfusion column (XR-010, Extracorporeal Medical Specialties) was shown to remove BCNU quantitatively from sheep blood flowing at 300 ml/minute when the drug was infused at 13 mg/minute for 30 minutes. Under general anesthesia, adult rhesus monkeys underwent catheterization of the internal carotid artery and placement of a catheter in the ipsilateral jugular vein at its junction with the sigmoid sinus. BCNU (10 mg/kg) was infused over 20 minutes while blood was pumped from the jugular vein through a small column and back into the inferior vena cava. The procedure reduced systemic exposure by 46%-84% compared with iv infusion of the same dose. Brain-to-systemic exposure ratios ranged from 18:1 to 87:1, depending on the pump flow rate and method of calculation. Hematopoietic toxicity was prevented. It is suggested that tumor exposure to BCNU comparable to that associated with very high tumor cell kill in vitro may be feasible with little or no systemic toxicity.
Oldfield
E H
EH
Dedrick
R L
RL
Chatterji
D C
DC
Yeager
R L
RL
Girton
M E
ME
Kornblith
P L
PL
Doppman
J L
JL
D000818:Animals; D001921:Brain / Q000187:drug effects; D001932:Brain Neoplasms / Q000097:blood / Q000188:drug therapy; D002330:Carmustine / Q000008:administration & dosage* / Q000097:blood / Q000633:toxicity; D002343:Carotid Artery, Internal; D005909:Glioblastoma / Q000097:blood / Q000188:drug therapy; D006464:Hemoperfusion; D007261:Infusions, Intra-Arterial; D007275:Injections, Intravenous; D007700:Kinetics; D008253:Macaca mulatta; D008954:Models, Biological; D012756:Sheep
D002330:Carmustine