RT Journal Article
SR Electronic
T1 Pharmacokinetic Advantage of Intra-arterial Cyclosporin A Delivery to Vascularly Isolated Rabbit Forelimb. I. Model Development
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1185
OP 1190
VO 289
IS 3
A1 Mansour V. Shirbacheh
A1 Xiaoping Ren
A1 Jon W. Jones
A1 Warren C. Breidenbach
A1 Anthony W. Jevans
A1 G. Rafael Fernandez-Botran
A1 Claudio Maldonado
A1 John H. Barker
A1 Scott A. Gruber
YR 1999
UL http://jpet.aspetjournals.org/content/289/3/1185.abstract
AB Effective antirejection therapy with minimal systemic morbidity is required if limb transplantation is to become a clinical reality. We investigated whether i.a. infusion of cyclosporin A (CSA) into the vascularly isolated rabbit forelimb will distribute drug homogeneously to the tissues and produce higher local drug levels than same-dose i.v. treatment, thereby improving the therapeutic index. CSA 4.0 mg/kg/day was infused continuously via osmotic minipump into either the right brachial artery (i.a. group) or jugular vein (i.v. group) of New Zealand rabbits. Ligation of all muscles at the right mid-arm level was performed in the i.a. group to eliminate collateral circulation and simulate allografting, while leaving bone and neurovasculature intact. On day 6, CSA concentrations were measured in skin, muscle, bone, and bone marrow samples taken from different compartments of the right and left forearms in the i.a. group and right forearm only in the i.v. group. There were no significant differences between compartmental CSA levels in all tissues examined on the locally treated, right side during i.a. infusion, indicating that drug streaming from the catheter tip is not occurring in our model. During i.a. infusion, mean CSA concentrations were 4- to 7-fold higher in the right limb than in the left limb in all four tissues examined. Tissue CSA levels in the left limb were equivalent to those achieved during i.v. infusion, but CSA concentrations in blood, kidney, and liver were higher during i.a. infusion. These favorable, preliminary, single-dose pharmacokinetic results warrant further investigation in our novel rabbit model. The American Society for Pharmacology and Experimental Therapeutics