Pharmacokinetics of intra-arterial delivery of tacrolimus to vascularly isolated rabbit forelimb

A vascularly isolated rabbit forelimb model simulating conditions of compos ite 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 b lood, heart, lung, liver, kidney, spleen, and fat, as well as in skin, musc le, bone, and bone marrow samples from both right and left forelimbs. The r elative tissue concentrations of FK506 in descending order were [spleen app roximate to lung approximate to kidney] > [heart approximate to skin approx imate to muscle] > [fat approximate to bone marrow] > [liver approximate to bone approximate to 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 al l forearm tissues over the dose range studied. For each limb tissue, left-s ided FK506 concentrations significantly correlated with systemic blood leve ls, and the left-sided tissue-to-whole-blood concentration ratio did not va ry significantly with dose. We conclude that FK506 is pharmacokinetically i nferior to cyclosporin A for continuous i.a. administration to the vascular ly isolated rabbit forelimb, and hypothesize that this difference is the re sult of differences in the distribution of each drug within whole blood. Ou r findings suggest that, despite its demonstrated efficacy in experimental and clinical transplantation, FK506 would not be an appropriate immunosuppr essant to deliver via the i.a. route for prevention of limb allograft rejec tion.