title: Pharmacokinetics of intra-arterial delivery of tacrolimus to vascularly isolated rabbit forelimb.
abstract: A vascularly isolated rabbit forelimb model simulating conditions of composite tissue allografting was used to determine the regional pharmacokinetic advantage achievable in extremity tissue components during i.a. tacrolimus (FK506) administration. FK506 was infused continuously via osmotic minipump into the right brachial artery of New Zealand rabbits at 0.05, 0.1, and 0.2 mg/kg/day. On day 6, FK506 concentrations were measured in aortic whole blood, heart, lung, liver, kidney, spleen, and fat, as well as in skin, muscle, bone, and bone marrow samples from both right and left forelimbs. The relative tissue concentrations of FK506 in descending order were [spleen approximately lung approximately kidney] > [heart approximately skin approximately muscle] > [fat approximately bone marrow] > [liver approximately bone approximately blood]. In marked contrast to previous results with i.a. cyclosporin A infusion, only a minimal regional advantage of local FK506 delivery (mean right/left concentration ratios 1.0-1.4) was obtained in all forearm tissues over the dose range studied. For each limb tissue, left-sided FK506 concentrations significantly correlated with systemic blood levels, and the left-sided tissue-to-whole-blood concentration ratio did not vary significantly with dose. We conclude that FK506 is pharmacokinetically inferior to cyclosporin A for continuous i.a. administration to the vascularly isolated rabbit forelimb, and hypothesize that this difference is the result of differences in the distribution of each drug within whole blood. Our findings suggest that, despite its demonstrated efficacy in experimental and clinical transplantation, FK506 would not be an appropriate immunosuppressant to deliver via the i.a. route for prevention of limb allograft rejection.
authors.affiliation: Division of Plastic and Reconstructive, University of Louisville School of Medicine, Louisville, Kentucky.
authors.forename: M V
authors.initials: MV
authors.lastname: Shirbacheh
authors.forename: J W
authors.initials: JW
authors.lastname: Jones
authors.forename: T A
authors.initials: TA
authors.lastname: Harralson
authors.forename: J
authors.initials: J
authors.lastname: Edelstein
authors.forename: T
authors.initials: T
authors.lastname: Tecimer
authors.forename: W C
authors.initials: WC
authors.lastname: Breidenbach
authors.forename: A W
authors.initials: AW
authors.lastname: Jevans
authors.forename: C
authors.initials: C
authors.lastname: Maldonado
authors.forename: J H
authors.initials: JH
authors.lastname: Barker
authors.forename: S A
authors.initials: SA
authors.lastname: Gruber
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D001842:Bone and Bones / Q000378:metabolism; D001916:Brachial Artery; D002406:Catheterization, Peripheral; D004305:Dose-Response Relationship, Drug; D005552:Forelimb / Q000098:blood supply; D007261:Infusions, Intra-Arterial; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism; D011817:Rabbits; D012867:Skin / Q000378:metabolism; D016559:Tacrolimus / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D014018:Tissue Distribution
chemical_list: D016559:Tacrolimus