PT  - JOURNAL ARTICLE
AU  - Mansour V. Shirbacheh
AU  - Xiaoping Ren
AU  - Jon W. Jones
AU  - Warren C. Breidenbach
AU  - Anthony W. Jevans
AU  - G. Rafael Fernandez-Botran
AU  - Claudio Maldonado
AU  - John H. Barker
AU  - Scott A. Gruber
TI  - Pharmacokinetic Advantage of Intra-arterial Cyclosporin A Delivery to Vascularly Isolated Rabbit Forelimb. I. Model Development
DP  - 1999 Jun 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1185--1190
VI  - 289
IP  - 3
4099  - http://jpet.aspetjournals.org/content/289/3/1185.short
4100  - http://jpet.aspetjournals.org/content/289/3/1185.full
SO  - J Pharmacol Exp Ther1999 Jun 01; 289
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